Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]([CH2:25][CH2:26]F)([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)[Br:29]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]([CH2:25][CH2:26][Br:29])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrB(Br)Br
Reactant: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCF)CC1
Solvent: ClCCl
Product: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCBr)CC1
Temperature: -5 °C

Procedure:
A solution of 2-benzyl-9a-(2-fluoroethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H)-one (3.2 g, 8.88 mmol) in 90 mL of dichloromethane was cooled to −65° C. and a 1M solution of boron tribromide in dichloromethane (27 mL, 27 mmol) was added dropwise during 15 minutes. The reaction mixture was allowed to warm to −5° C. during 30 minutes and was then partitioned between EtOAc and 5% aqueous NaHCO3. The organic phase contained some solid material which was dissolved by addition of dichloromethane and methanol. The organic layer was washed with water and brine and dried over MgSO4. Evaporation under vacuum gave 2-benzyl-9a-(2-bromoethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H)-one as an orange solid which was dissolved in THF (175 mL). The resulting solution was cooled to −65° C. and a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (22 mL, 11 mmol) was added dropwise during 15 minutes. The reaction mixture was allowed to warm to −5° C. during 25 minutes at which point HPLC analysis of an aliquot showed a small amount of unreacted starting material. An additional portion of 0.5M potassium bis(trimethylsilyl)amide in toluene (1 mL, 0.5 mmol) was added and the cooling bath was removed. After 15 minutes more, the reaction was quenched by the addition of 1N HCl (30 mL). The reaction mixture was partitioned between EtOAc and water and the organic phase was washed with 5% aqueous NaHCO3 and brine dried over MgSO4. Concentration of the organic solution under vacuum gave a precipitated solid which was isolated by filtration to give 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one. The filtrate was concentrated under vacuum and the residue chromatographed on silica gel (elution with 2:3 to 1:1 EtOAc/hexanes) to yield additional 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[CH:22]12[CH2:27][CH:26]1[CH2:25][N:24]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1)[CH2:23]2>>[CH:26]12[CH2:27][CH:22]1[CH2:23][N:24]([C:28]1[N:29]=[CH:30][C:31]([NH:34][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])=[CH:32][CH:33]=1)[CH2:25]2
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC3CC3C2)nc1
Product: O=C(Nc1ccc(N2CC3CC3C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 73.6 %

Procedure:
The process is carried out according to the method described in example 2, using 0.15 g (0.52 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 0.1 g (0.57 mmol) of 2-(3-azabicyclo[3.1.0]hex-3-yl)-5-aminopyridine, prepared in step 12.2. 0.17 g of the expected product is thus isolated.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH:10]([CH2:13][OH:14])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:14][CH2:13][CH:10]2[CH2:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[O:11]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1cccc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc([N+](=O)[O-])c3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol (3.14 g, 16.09 mol) in dichloromethane (100 mL) was added diisopropylethyl amine (4.16 g, 32.18 mmol), N,N-dimethylaminopyridine (0.39 g, 3.2 mmol), and p-toluenesulfonyl chloride (4.6 g, 24.13 mmol) the reaction was allowed to stir at room temperature for 12 h. The reaction was diluted with dichloromethane (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, dichloromethane: hexanes 3:10) afforded 5.2 g (94%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as off-white solid. mp 129-131° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][Si:22]([CH3:24])([CH3:23])[C:25]#[C:26][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-3-(propylsulfonyl)benzene (Intermediate 5; 23 g, 88 mmol) in THF (450 ml) was treated with Pd(dppf)Cl2 (3.9 g, 5.3 mmol), triethylamine (13.4 g, 132 mmol) and trimethylsilyl acetylene (8.64 g, 88 mmol). The reaction mixture was stirred at RT for 10 minutes, then cuprous iodide (1.0 g, 5.3 mmol) was added, the reaction mixture was heated at 60° C. for 24 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (98:2) as a eluent to afford the title compound as a brown oil.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C:23]1[C:27](B(O)O)=[CH:26][N:25]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:27]4[C:23]([CH3:22])=[N:24][N:25]([C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:26]=4)=[CH:4][CH:5]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1

Procedure:
4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride was reacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LC/MS: (PS-B3) Rt 2.78 min [M+H]+594. *This starting material can be made by the method described in EP1382603
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](OC)=[O:23]>C1COCC1.C(O)(=O)C.O>[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](=[O:23])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CC(=O)c1ccccc1Cl)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of n-butyl lithium in hexane (1.58N, 55.6 ml, 88 mmol) was added dropwise to a solution of dimethyl methylphosphonate (10.9 g, 88 mmol) in 100 ml of anhydrous THF with stirring at -78° C. under argon atmosphere. After 30 minutes, a solution of methyl o-chlorobenzoate (6.0 g, 35.2 mmol) in 10 ml of anhydrous THF was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-o-chlorophenyl-2-oxoethylphosphonate (8.2 g, 31.2 mmol, yield 88.7%, b.p. 142°-145° C./0.09 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O1[CH2:13][C:12](=O)[N:11]=[C-]1.C(=O)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:13][CH2:12][NH2:11])=[CH:4][CH:3]=1
Reactant: O=C1CO[C-]=N1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C=O
Product: NCCNc1ccc(Cl)cc1
Temperature: 160 °C
Yield: 70.9 %

Procedure:
The hydrochloride salt of 4-chloroaniline (6.2 g, 38 mmol) and 2-oxazolidone (3.29 g, 38 mmol) was suspended in a minimal amount of di(ethyleneglycol)methyl ether amd the resulting suspension heated at 160° C. After 4 h CO2 evolution ceased and the reaction mixture was cooled to ambient temperature. The resulting solid was crystallized from EtOH/ether to yield 4.6 g (58%) of 4-chloroanilinoethylamine as its HCl salt. MS CI (M+H)+ at m/z 171. The free amine was prepared by partitioning the HCl salt between CH2Cl2 and NaHCO3 (sat.), drying the organic layer (Na2SO4), filtering and concentrating.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=[O:29]>>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][O:29][C:20]1[CH:19]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: COc1ccc(Br)c(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-bromo-5-methoxylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 531.1.
Reaction SMILES: C(C=C)=O.C(=O)C=CC1C=CC=CC=1.C(=O)/C=C/C.C(SC(C)C=O)CCCCCCCCCCC.[CH2:37]([S:49][CH:50]([CH2:53][C:54]1C=CC=CC=1)[CH:51]=[O:52])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH2:37]([S:49][CH:50]([CH2:53][CH3:54])[CH:51]=[O:52])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCSC(C=O)Cc1ccccc1
Agent: C/C=C/C=O
Agent: C=CC=O
Agent: CCCCCCCCCCCCSC(C)C=O
Product: CCCCCCCCCCCCSC(C=O)CC

Procedure:
If in the above reaction acrolein or cinnamaldehyde are used in place of crotonaldehyde, n-dodecylthiopropanal and n-dodecylthio-3-phenylpropanal respectively are obtained.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][OH:26]>>[CH2:10]([O:9][C:8]([NH:7][C@@H:4]([CH2:25][OH:26])[CH2:3][C:2]([O:6][CH3:5])=[O:1])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(R)-Benzyl 5-oxotetrahydrofuran-3-ylcarbamate (INTERMEDIATE 3, 27.0 g, 114.78 mmol) was dissolved in methanol (75 ml) and triethylamine (75 ml) was added at room temperature. The resulting mixture was allowed to stir overnight at this temperature. The mixture was concentrated in vacuo to provide the title product. This material was used to prepare INTERMEDIATE 5 without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1

Procedure:
To a solution of N-(4-nitrophenyl)piperidine (12 g) in methanol (50 ml) was added conc. hydrochloric acid (12 ml) and, by using 10% palladium/carbon as a catalyst, catalytic reduction was conducted at normal temperature and normal pressure. After completion of the reaction, the catalyst was removed and the solvent was distilled off. To the residue was added ethyl ether which was filtered off to obtain N-(4-aminophenyl)piperidine dihydrochloride (13.7 g) as a colorless solid.
Reaction SMILES: [OH-].[K+].[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)O.[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].C(O)(=O)C>COCCO.C(OCC)(=O)C>[OH:7][C:6]1[CH:8]=[C:9]([OH:10])[C:11]2[CH:20]3[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:12](=[O:14])[CH2:13][C:3]=2[CH:5]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(=O)C1=CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Cc2cc(O)cc(O)c2C2CCCCC12
Temperature: 140 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere, there is added 50 g. (0.89) moles of potassium hydroxide in one liter of 2-methoxyethanol. Stirring is initiated and 100 g. (0.79 mole) of anhydrous phloroglucinol is added in three portions, followed by the addition of 100 g. (0.80 mole) of 1-acetyl-cyclohexene while maintaining the temperature at 50° C. The resulting solution is refluxed at 140° C. for 4 hours. After cooling there is then added gradually 53.6 g. of acetic acid while obtaining a pH of approximately 7. The solvent is then removed in vacuo, and the residue is further heated in an oil bath at 70° C., to obtain a viscous residue. The resulting residue is dissolved in ethyl acetate and water washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to obtain a brown solid. The resulting solid is recrystallized from ethyl acetate/cyclohexane to give 2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene; m.p. 220°-223° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41].[NH2:42][CH:43]1[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F
Product: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(NC4CCNCC4)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate: LC-MS m/z 599 (M+H)+, 1.98 min (ret time).
Reaction SMILES: [CH3:1][N:2]1[C:6](=S)[CH2:5][CH2:4][C@@H:3]1[CH2:8][C:9]#[N:10]>[Ni].CCO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][C:9]#[N:10]
Reactant: CN1C(=S)CC[C@@H]1CC#N
Agent: [Ni]
Solvent: CCO
Product: CN1CCC[C@@H]1CC#N

Procedure:
Raney-Ni (1.5 ml) was added to an EtOH (30 ml) solution of the 2-((2R)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (1.36 g, 8.8 mmols), and the mixture was heated for 24 hours under reflux (Upon TCL, the starting materials had not completely disappeared). The inorganic matter was filtered off, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (SiO2 40 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2R)-1-methylpyrrolidin-2-yl)ethanenitrile as a mixture (498 mg) with impurities difficult to separate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[C:2]1[C:14]([OH:16])=O.[CH3:17][CH:18]([NH:20][C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH3:19][CH:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:14]([C:2]2[NH:1][C:9]3[C:8]4[C:7]([CH:6]=[CH:5][C:4]=3[CH:3]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[O:16])[CH2:31][CH2:32]1)[CH3:17]
Reactant: O=C(O)c1cc2ccc3ccccc3c2[nH]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3ccc4ccccc4c3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with benz[g]indole-2-carboxylic acid (PREPARATION 112, 0.3 g) and 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (PREPARATION 9, 0.34 g), the title compound is obtained, m.p. 190°.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[S:21]1[C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CS
Reactant: O=Cc1ccncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccncc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a 50-mL round-bottom flask was added 3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and N,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. To this solution was added potassium carbonate (1.22 g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned to a clear yellow solution after stirring for 10 min. After 30 min at 0° C., the reaction was warmed to room temperature and stirred over the weekend by which time a solid precipitate was formed. Water was added provide a homogeneous solution, which was cooled to 0° C., the solid was collected via vacuum filtration, and washed with cold water until clear and colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; 1H NMR (d6-DMSO, 300 MHz) δ9.37 (s, 1 H), 8.56 (d, J=5.4 Hz, 1 H), 8.26 (d, J=0.6 Hz, 1 H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1 H), 3.92 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:16]=3[O:15][CH3:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: COc1ccc(OC)c(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(OC)c(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 17.9 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (155 mg, 0.597 mmol), 2,5-dimethoxybenzylamine (0.096 mL, 0.636 mmol), Pd2(dba)3 (61 mg, 0.067 mmol), rac-BINAP (111 mg, 0.178 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,5-dimethoxy-benzylamino)-2H-phthalazin-1-one (37 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 3.45 (s, 3H), 3.61 (s, 3H), 4.17 (d, 2H), 6.63 (m, 3H), 6.76 (d, 1H), 6.94 (dd, 1H), 7.33 (t, 1H), 7.72 (d, 1H), 12.14 (s, 1H) ppm; m/z (M+1) 345.92.
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.C1(NN)C=CC=CC=1>>[ClH:1].[Cl:1][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: NNc1ccccc1
Product: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 4-chlorophenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13](=O)[C:14]3[N:15]([N:17]=[CH:18][CH:19]=3)[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:23])=O>O>[Cl:23][C:13]1[C:14]2[N:15]([N:17]=[CH:18][CH:19]=2)[CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:12]=1
Reactant: COc1ccc(-c2cn3nccc3c(=O)[nH]2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2cn3nccc3c(Cl)n2)cc1OC
Temperature: 95 °C

Procedure:
6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 5.02 (74 mg, 0.27 mmol) was taken up in phosphorous oxychloride (1.4 mL, 15 mmol) and mixture was heated to 95° C. for two hours. After cooling to room temperature, mixture was carefully added via pipet to vigorously stirring water (15 mL) with internal temperature monitoring, at a rate to keep the internal temperature below 45° C. Reaction flask was washed with 15 mL of ethyl acetate and added to aqueous mixture to ensure complete transfer. Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were washed with 1:1 brine/saturated NaHCO3 (aq), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 4-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazine 5.03. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H13ClN3O2: 290.06; found: 290.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=2)[CH:7]=1.O.[OH-].[Li+].O.C1COCC1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(F)cn12
Temperature: 65 °C
Yield: 100.6 %

Procedure:
Ethyl 6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (0.10 g, 0.48 mmol) and lithium hydroxide monohydrate (0.020 g, 0.48 mmol) were added to a mixture of water, THF and ethanol (1:2:1) and heated in a sealed vial at 65° C. for 6 hours. The solvent was removed by rotary evaporation to yield 87 mg of the desired product. MS (ES+APCI) m/z=181.1 (M+H).