Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N+:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][NH:21][CH2:22]2)([O-:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[CH:26][C:17]=4[N+:14]([O-:16])=[O:15])[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: O=[N+]([O-])c1cccc2c1CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(cccc2[N+](=O)[O-])C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH2:22])[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:22][CH:21]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: NC1CCCCc2ccccc21
Reactant: Clc1nc2ccccc2[nH]1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCCCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylamine (prepared by Procedure B from 1-benzosuberone) by Procedure A (reflux in toluene for 2 days). The product was isolated from the reaction mixture by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 203-205° C.). MS(ES+) m/z 278 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.28-1.39 (m, 1H), 1.65-2.02 (m, 5H), 2.83-2.97 (m, 2H), 5.03 (t, 1H), 6.77-6.89 (m, 2H), 7.05-7.29 (m, 7H), 10.6 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12>CN(C=O)C>[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccncc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(Cl)c2ccncc12
Temperature: 55 °C
Reaction time: 17 h

Procedure:
4,4-difluorocyclohexanecarboxylic acid (277 mg, 169 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (411 mg, 1.61 mmol) were stirred in DMF (3 ml) and triethylamine (0.4 ml) for 2 minutes. The solution was added to (R)-1-chloro-4-(2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 59 (387 mg, 1.47 mmol) and washed in with an additional 1 ml DMF. The reaction was heated at 55° C. for 1.5 hours and then stirred at RT for 17 hours. The reaction was added to saturated NaHCO3 (80 ml) and extracted three times with dichloromethane (50 ml). The combined organics were dried (MgSO4) and evaporated to give a yellow solid. The residue was chromatographed over silica with a gradient of hexane and 0-100% ethyl acetate to give (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 as a yellow solid, 236 mg. LC/MS m/z=410 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH2:50][CH2:51]O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:53]([OH:56])(=[S:55])[CH3:54]>O1CCCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH2:50][CH2:51][S:55][C:53](=[O:56])[CH3:54])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCC1CCCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (3.99 g in 35 mL dry tetrahydrofuran) was added 3.0 mL diisopropyl azodicarboxylate and the mixture stirred at 0° C. for 30 minutes. At this time, 2.0 g of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester was added followed by the dropwise addition of a solution of 1.16 g thioacetic acid in 19 mL tetrahydrofuran. After 2 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:methylene chloride, 1:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[Li+].[OH-].Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)CCc1nc(I)c2c(Cl)nccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1nc(I)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 74A (1.96 g) in tetrahydrofuran (5 mL) and ethanol (1 mL) was treated with 2N LiOH (5.16 ml), stirred at room temperature for 3 hours and then neutralized to pH 3-4 with 3N HCl. The mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4) and concentrated to dryness to give the title compound. MS (ESI(+)) m/e 352 (M+H)+.
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]3[CH2:16]CC[C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1[C:20](O)=[O:21]>>[CH3:20][O:21][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2
Product: COc1cccc2c1C(=O)N(C)CC(=O)N2

Procedure:
(S)-6-methyl-1,2,3,11a-tetrahydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine-5,11 (10H)-dione by reaction with L-proline. M.p. 207.6°-209.9° C.
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH3:7][C:8]([CH3:16])([CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:9]#N>C1(C)C=CC=CC=1>[C:14]([CH:13]1[C:7](=[O:4])[C:8]([CH3:16])([CH3:9])[CH2:11][CH2:12]1)#[N:15]
Reactant: CC(C)(C#N)CCCC#N
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C#N)C1=O
Reaction time: 2 h
Yield: 55 %

Procedure:
A suspension of potassium t-butoxide (60.2 g, 0.54 mole) in toluene is treated with 2,2-dimethyladiponitrile (120.7 g, 0.87 mole) at 80° C., stirred for 2 hours, cooled to less than 30° C., and quenched with water. The phases are separated, the organic phase is stirred with 3N hydrochloric acid and filtered. The filtrate is concentrated in vacuo to give an oil which is distilled (2 torr, 150° C.) twice to afford the title product as a colorless oil, 65.7 g (98.5% pure, 55% yield), identified by gas chromatography.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[S:24][CH:25]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[S:24][CH:25]=[C:21]([CH2:20][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH:1]2[CH2:2][CH2:3]2)[N:22]=1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: ClCc1csc(-c2ccccc2Cl)n1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2csc(-c3ccccc3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(chloromethyl)-2-(2-chlorophenyl)-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 8.18 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.49 (m, 2H), 7.37 (m, 2H), 6.82 (s, 1H), 6.47 (s, 1H), 5.70 (s, 2H), 2.02 (m, 1H), 1.08 (m, 2H), 0.87 (m, 2H); MS (ES) m/z 458 (M+1) and 460 (M+1, isotope).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[C:11]([Cl:13])[N:12]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccccc2)n1
Yield: 69.1 %

Procedure:
A stirred mixture of 8.0 g of (4.6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 2.8 g of aniline and 3.2 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to start precipitation. The crude product was recrystallized from 95% ethanol to afford 6.7 g of product, mp. 109°-114°C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17]>>[O:20]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19])[CH2:6][C:2]#[N:1]
Reactant: COC(=O)c1ccccc1C(F)(F)F
Reactant: Nc1cc[nH]n1
Product: N#CCC(=O)c1ccccc1C(F)(F)F
Yield: 94 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-trifluoromethyl-benzoic acid methyl ester (3.1 g, 14.0 mmol, 1.0 eq). The crude was precipitated from HCl to give the title product as a yellow solid (2.8 g, yield: 94%).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C@:21]3([C:37](=[O:39])[NH2:38])[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:36])[C@@H:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:28]([CH3:30])[CH3:29])=[C:17]([N+:40]([O-])=O)[CH:16]=2)[CH2:13][CH2:12][C@@H:11]1[C:43]1[CH:48]=[CH:47][C:46]([C@:49]2([C:65](=[O:67])[NH2:66])[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[C:45]([N+:68]([O-])=O)[CH:44]=1>O1CCCC1.[Ni].O>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[N:10]1[C@@H:11]([C:43]2[CH:48]=[CH:47][C:46]([C@:49]3([C:65](=[O:67])[NH2:66])[CH2:53][CH2:52][CH2:51][N:50]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[C:45]([NH2:68])[CH:44]=2)[CH2:12][CH2:13][C@@H:14]1[C:15]1[CH:20]=[CH:19][C:18]([C@:21]2([C:37](=[O:39])[NH2:38])[CH2:25][CH2:24][CH2:23][N:22]2[C:26](=[O:36])[C@@H:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:28]([CH3:29])[CH3:30])=[C:17]([NH2:40])[CH:16]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c([N+](=O)[O-])c3)N2c2nc3c(s2)CCCC3)cc1[N+](=O)[O-])C(C)C
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c(N)c3)N2c2nc3c(s2)CCCC3)cc1N)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 116E (0.59 g, 0.596 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney Nickel slurry in water (0.25 mL). The flask was evacuated and opened to a hydrogen balloon and stirred at ambient temperature for 1 hour. The solution was filtered through a silica plug and concentrated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>>[CH2:17]([N:13]1[CH2:12][CH:11]=[C:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=3[N:7]=2)[CH2:15][CH2:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ccc2sc(-c3ccncc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc2sc(C3=CCN(Cc4ccccc4)CC3)nc2c1
Yield: 65.5 %

Procedure:
4-(5-Chlorobenzothiazol-2-yl)pyridine (1.8 g, 7.3 mmol) was reacted with benzyl bromide (1.3 ml, 10.95 mmol), followed by sodium borohydride (361 mg, 9.5 mmol) as exemplified in Example 7 step 2. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give a solid. Recrystallisation from ethyl acetate afforded the title compound as a pale yellow solid (1.63 g, 66%); (Found: C, 66.83; H, 5.00; N, 8.20. C19H17ClN2S requires C, 66.95; H, 5.03; N, 8.22%). δH (CDCl3), 2.76 (4H, m, CH2), 3.24 (2H, m, CH2), 3.67 (2H, s, NCH2Ar), 6.70 (1H, m, NCH2CH), 7.32 (5H, m, ArH), 7.71 (1H, d, J 8.5Hz, ArH), 7.95 (1H, d, J 1.9Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:21]([NH:23][NH2:24])=[O:22])=[CH:14][N:15]([CH3:20])[C:16](=[O:19])[C:17]=2[F:18])=[C:7]([F:25])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:22][C:21]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:25])=[C:17]([F:18])[C:16](=[O:19])[N:15]([CH3:20])[CH:14]=2)=[N:23][N:24]=1
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nnc(N)o2)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 17 h
Yield: 89.2 %

Procedure:
Cyanogen bromide (36 mg, 0.31 mmol) was added to a suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (63 mg, 0.169 mmol) in dioxane (2 mL) followed by an aqueous NaHCO3 (2 mL of a 0.09 M solution) solution. After 17 hours, additional cyanogen bromide (14 mg) was added. After 19; hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Crystallization (MeOH:THF) followed by trituration (Et2O:MeOH 5:1) gave clean desired product as a white solid (60 mg, 89%). MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.06 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.10 (td, 1H), 3.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[CH:29]=[C:28]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:27]=[N:26][CH:25]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1c(-c2cncc(Br)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (80 mg, 0.264 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 188 mg, 0.792 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.320 mL, 0.63 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (144 mg, 0.016 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) tilt 333.0246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3(O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCOCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
Add to a solution of 4-[3-(4-hydroxy-tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methyl ester (20.0 g, 48.19 mmol) in anhydrous methylene chloride (500 mL) at room temperature, triethylsilane (20.0 mL, 125.19 mmol) and trifluoroacetic acid (61.5 mL, 798.2 mmol). Stir the resulting solution for 1 h, concentrate, and obtain the oil and partition between ethyl acetate (500 mL) and saturated sodium bicarbonate (500 mL). Dry the organic layer over sodium sulfate, filter through a silica gel pad, and back-wash with ethyl acetate (400 mL). Concentrate the filtrate to low volume, add hexanes, and a separate the solid. Filter the solid and hold aside, 14 g. Concentrate the filtrate to low volume and add MTBE to provide a second crop of crystals, filter and found identical by TLC (3:2 hexanes/ethyl acetate) to the original lot, 2.8 g. Combine the two lots and dry (20 mmg Hg, 40° C.) to provide one lot of highly pure title compound for subsequent hydrolysis (16.8 g, 87%); 1H NMR (DMSO-d6) δ 8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 3.94 (m, 2H), 3.85 (s, 3H), 3.50 (t, J=11.5 Hz, 2H), 3.03 (m, 1H), 1.86 (m, 2H), 1.70 (m, 2H); MS(ESI) m/z 400 (m+H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Yield: 41.2 %

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 14.25 g of 1-bromo-4-(trifluoromethyl)benzene in 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF. This gives 7.3 g of the expected product.
Reaction SMILES: Cl[C:2]1[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[N:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:33]1>>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[NH:3][C:2]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:33]3)=[N:12][C:5]=2[CH:6]=[N:7]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: Cn1ncc2c(nc(Cl)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Product: Cn1ncc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)[nH]c2c1=O
Temperature: 150 °C
Yield: 98 %

Procedure:
0.020 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazine-4-one and 0.040 g of t-butyl piperidin-3-ylcarbamate were combined together, and the mixture was heated under a nitrogen atmosphere at 150° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography. Thus, 0.016 g of t-butyl [1-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperidin-3-yl]carbamate was obtained from the fraction eluted with ethyl acetate. 0.0080 g of this compound was dissolved in 0.6 ml of N,N-dimethylformamide, and then 0.0038 g of potassium carbonate and 0.003 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1 ml of ethyl acetate and 1 ml of water, and the organic layer was concentrated. The residue was dissolved in 0.5 ml of dichloromethane, and then 0.5 ml of trifluoroacetic acid was added thereto. After 1 hour, the reaction solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0046 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:28]1[C:37]2[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:28]2[C:37]3[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=3)[N:31]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)[CH:29]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 8 h
Yield: 116.4 %

Procedure:
A solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ester (500 mg, 1.5 mmol), prepared as described in WO2005/073195, 4-hydroxy-2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinoline (97, 504 mg, 1.8 mmol) and triphenylphosphine (990 mg, 3.75 mmol) were stirred in dry THF (40 mL) at 0° C. for 10 min. Then, DIAD (0.74 mL, 3.75 mmol) was added drop wise. The resulting reaction mixture was stirred at a temperature from 0° C. to 22° C. overnight. Then, volatiles were evaporated and the residue was purified by column chromatography on silica gel (gradient CH2Cl2/AcOEt, 1:0 to 95:5) to give 1.1 g (88%) of the title compound 98: m/z=630 (M+H)+.
Reaction SMILES: [Na:1].[CH:2](OCC)=[O:3].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8]>CO>[Na:1].[CH3:13][O:12][C:10](=[O:11])[C:9](=[CH:2][OH:3])[C:7]#[N:8]
Reactant: COC(=O)CC#N
Reactant: CCOC=O
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)=CO
Yield: 61.2 %

Procedure:
Sodium metal (11.8 g, 0.511 mol) was dissolved in 450 mL of methanol and to this warm solution was added a solution of ethyl formate (104 g, 1.41 mol) and methyl cyanoacetate (43.8 g, 0.440 mol) over two minutes. A small amount of precipitate formed during the addition. The reaction mixture was heated to reflux and maintained there for 1.5 hours. The thick white suspension was allowed to cool to 20° C.-25° C. and the precipitate was filtered, washed with diethylether, and dried in vacuo at 45° C. to give 40.4 g (61.6%) of the title compound which was of sufficient purity for use in Preparation 6.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH:14]=1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:18]=[CH:17][N:16]=2)=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Br)ccn1
Reactant: CSc1ncc2c(n1)CNC2
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccc(C(F)(F)F)cc3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 4-Bromo-N-(4-(trifluoromethyl)phenyl)picolinamide were converted to the title compound.