Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3].P(Br)(Br)[Br:16]>C(OCC)C>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:16])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCOc1ccc(CO)cc1OC
Solvent: CCOCC
Product: CCCOc1ccc(CBr)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.3 %

Procedure:
To a solution of 4-(propyloxy)-3-methoxybenzyl alcohol (2.28 g, 11.62 mmol) in anhydrous diethyl ether (30 mL) was slowly added PBr3 (0.55 mL, 5.81 mmol) via syringe, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 4-(propyloxy)-3-methoxybenzyl bromide (2.94 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:28])=O.CN(C)C=O>ClCCl>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([Cl:28])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
(4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 39 (0.05 mol) was dissolved in dichloromethane (50 mL) and thionyl chloride (5 mL) and dimethylformamide (0.1 mL) were added. After 2 hours, the solvents were removed under vacuum to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetyl chloride, 123. This compound (0.01 mol) was dissolved in ether (25 mL) and the solution was cooled to −80° C. and lithium aluminum tri-tertiarybutoxy hydride (0.01 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was warmed to room temperature and water was added. The organic phase was dried and concentrated and the residue was chromatographed to afford the title compound 124.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@H]1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 74%), MS (ISP) m/z=459.5 [(M+H)+], mp 181° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) (S)-2-(1,4-dioxan-2-yl)acetic acid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:55]1[CH:64]=[C:63]2[C:58]([CH:59]=[CH:60][C:61](=[O:65])[O:62]2)=[CH:57][CH:56]=1>C1COCC1>[O:65]=[C:61]1[CH:60]=[CH:59][C:58]2[C:63](=[CH:64][C:55]([O:13][CH2:14][CH2:15][O:16][C:17]3[C:18]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[N:19][S:20][N:21]=3)=[CH:56][CH:57]=2)[O:62]1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCOc2ccc3ccc(=O)oc3c2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 123.6 %

Procedure:
Diethyl azodicarboxylate (DEAD; 61 μl, 0.39 mmol) was added dropwise to a mixture of the product obtained in Step 2 (100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol) and 7-hydroxycoumarin (63 mg, 0.39 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 5 days. After solvent removal, the residue was purified by chromatography on silica gel eluting with hexane/EtOAc (1:1) to give the title product as a white solid (176 mg) which had low purity (67% by HPLC). This material was used directly in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10]2[S:11][C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=3)=[CH:13][C:9]=2C=[CH:7][CH:6]=1.[NH4+:30].[Cl-].O>CCO.[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:6]=[CH:7][N:30]=[C:9]3[CH:13]=[C:12]([C:14]4[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=4)[S:11][C:10]=23)=[C:2]([F:1])[CH:26]=1
Reactant: [NH4+]
Reactant: CC(=O)N1CC=C(c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 90.4 %

Procedure:
To a mixture of the nitro compound 390 (358.2 mg, 0.87 mmol) and NH4Cl (39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. Fe powder (411.3 mg, 7.36 mmol) was added in one portion and the mixture was heated to reflux under vigorous stirring for 40 min. It was then filtered through Celite®, the Celite® was washed with EtOH and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, dried (anhydrous Na2SO4) and concentrated under reduced pressure affording 391 (256.5 mg, 77% yield) as a white solid. LCMS:(M+H) 384.2.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)=CC=1)([O-])=O.[CH3:19][NH:20][CH2:21][CH2:22][N:23]([CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:19][N:20]([CH2:21][CH2:22][N:23]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:60][CH:61]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[C:9](=[O:8])[O:11][CH2:12][C:13](=[O:14])[O:15][CH3:16]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)N(CCN(C)C(=O)OCC(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
A mixture of 100 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate and 5.0 mL of THF was added to a mixture of 180 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.15 mL of N-ethyl-N-isopropylpropan-2-amine, and 5.0 mL of THF under ice cooling, followed by stirring for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane:chloroform=4:6), thereby obtaining 204 mg of methyl 4-{2-[4-({[2-({3-[7-methyl-3,6-dioxo-10-(pentan-3-yl)-2,5-dioxa-7,10-diazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cn(-c2cccc(Br)c2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1ccccc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: 70 °C

Procedure:
A solution of 7 (250 mg, 0.76 mmol), phenylboronic acid (102 mg, 0.84 mmol) and Na2CO3 (244 mg, 2.3 mmol) in DME/H2O 4:1 (10 mL) was thoroughly purged with argon, after which Pd(PPh3)2Cl2 (36 mg; 0.05 mmol) was added and the mixture was heated to 70° C. for 21 h. The solvents were removed in vacuo and the residue was purified by column chromatography (1 to 5% methanol in CH2Cl2 to give 100 mg (41%) pure 8. HRMS (ESI+): m/z=324.3814 [M+H]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:15]3[CH:14]4[CH2:16][CH:13]4[CH2:12][C:11]=3[C:10]([C:17]([O:19]CC)=[O:18])=[N:9]2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nn(CC2CCOCC2)c2c1CC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nn(CC2CCOCC2)c2c1C[C@H]1C[C@@H]21
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
Ethyl 2-((tetrahydro-2H-pyran-4-yl)methyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylate (127 mg, 0.437 mmol) was dissolved in THF (4.00 mL) and H2O (4.00 mL). Lithium hydroxide hydrate (55.1 mg, 1.312 mmol) was added and the reaction was stirred at 45° C. for 1.5 h. The organic solvent was removed under reduced pressure to give the title compound (115 mg) as a brown solid. LCMS m/z=263.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:30][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:30][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Yield: 29 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (1.20 g, 1.99 mmol), TFA (2 mL) and DCM (20 mL) to afford 0.280 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.85 (s, 3H), 4.46 (d, J=6.0 Hz, 2H), 7.51 (t, J=8.1 Hz, 1H), 7.65-7.68 (m, 3H), 7.78-7.84 (m, 2H), 10.09 (m, 1H), 12.70 (br s, 1H); MS (m/z): (M)+ 484.95.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C:20](Cl)(=[O:24])[C:21]([Cl:23])=[O:22]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:20](=[O:24])[C:21]([Cl:23])=[O:22])=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cn1c(COc2ccc(Cl)cc2)c(C(=O)C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methyl-2-(4-chlorophenoxymethyl)-1H-indole (1.00 g, 3.68 mmol), dissolved in 7.0 ml of diethyl ether in a round bottom flask under a nitrogen atmosphere. To the above solution was added oxalyl chloride (0.981 g, 7.73 mmol). The reaction mixture was stirred at room temperature for about 60 minutes. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][N:10]1[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]1=[O:22])[CH2:6]2.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH:7]3[CH:3]([CH:2]3[NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CC3C(N)C3C1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CC3C(C1)C3NCc1ccc3c(n1)NC(=O)CO3)C(=O)CO2
Yield: 6 %

Procedure:
4-[2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 93), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 6% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([S:11][CH2:12]C)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:12][S:11][C:9]1[O:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SCC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc(C(=O)O)o1
Temperature: 80 °C

Procedure:
To a solution of 2-ethylsulfanyl-oxazole-5-carboxylic acid ethyl ester (4.6 g, 24.57 mmol) in ethanol (100 mL) was added a 2 N solution of sodium hydroxide (37 mL, 74 mmol) in water. The mixture was heated at 80° C. for 4 hours and then concentrated in vacuo to remove the ethanol. The remaining aqueous solution was then acidified with 1 N HCl and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 2-methylsulfanyl-oxazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.C1(C)C(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=CC=1.CC(C)([O-])C.[K+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:20]#[N:21])[CH2:6][CH2:5]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: COCC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: COCC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−10° C.) solution of EXAMPLE 374C (1.18 g) and toluenesulfonylmethyl isocyanide (2.268 g) in dimethoxyethane (3 mL) and absolute ethanol (0.1 mL) was added (in small portions) potassium tert-butoxide (2.235 g). The reaction mixture was continued to stir at <5° C. for 30 minutes, warmed to room temperature, heated at 35° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in water-brine, and extracted with dichloromethane. The dichloromethane layer was purified by flash chromatography, and was eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])=[O:19])[CH2:14][CH2:13]1.FC(F)(F)C([O-])=O.[OH-].[Na+]>CC#N.O>[Cl:10][C:4]1[CH:5]=[C:6]([NH:8][CH3:9])[N:7]=[C:2]([NH:11][C@@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:29])([F:30])[F:31])=[O:19])[CH2:16][CH2:17]2)[N:3]=1
Reactant: CNc1cc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1cc(Cl)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1

Procedure:
To a solution of 2,6-dichloro-N-methyl-4-pyrimidinamine (360 mg, 2.0 mmol) and cis-4-amino-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (Intermediate 1) trifluoroacetate (829 mg, 2.0 mmol), in MeCN/H2O (1:1, 5 mL) was added 1N NaOH solution until a pH of 12 was achieved. The mixture was irradiated in the microwave for 4 hours at 170° C., at which time LCMS indicated the formation of the desired product. The reaction mixture was extracted with EtOAc (2×50 mL), washed with water (2×50 mL), dried (Na2SO4), and concentrated to afford a waxy solid. The crude material was purified by column chromatography (Gradient from 0-5% MeOH in CH2Cl2) to afford 300 mg (0.68 mmol, 34%) of a colorless wax MS (ES+) m/e 442 [M+H]+. Regiochemistry was verified by 2D NMR analysis.
Reaction SMILES: O[C:2]1([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:11])[CH:9]=2)[NH:4][C:3]1=O.B(F)(F)F.CCOCC>COCCOC>[I:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH2:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15]
Reactant: CN(C)C(=O)CC1(O)C(=O)Nc2ccc(I)cc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: COCCOC
Product: CN(C)C(=O)Cc1c[nH]c2ccc(I)cc12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a suspension of 2-(5-iodo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 6) (36.0 g, 0.1 mol) in DME (250 mL), at 20° C. boron trifluoride etherate (28.3 g, 0.2 mol) is added. Under cooling with an ice bath, borane dimethyl sulfide complex (12.0 g, 0.15 mol) is added during 10 minutes, and then the cooling bath is removed. The temperature rises slowly to 55° C., and a suspension forms at about 50° C. When the exothermic reaction has subsided, the mixture is stirred at 75° C. for another 30 minutes, and then quenched by adding 4 N NaOH (100 mL). The mixture is heated under reflux for another 30 minutes, and then filtered while still hot. Removal of the solvent on the rotavapor leads to crystallization of the product, which goes to completion on standing in the refrigerator for 12 hours. The product is filtered off, washed with cold acetone (50 mL, −20° C.) and pentane, and dried to give the title product (24.8 g, 75%) as crystals, mp.=195-200° C. 1H-NMR (DMSO-D6, 300 MHz) δ 2.80, 2.99 (2 s, 3H each, N(CH3)2); 3.69 (s, 2H, CH2); 7.19 (d, 1H, 3J=2.4 Hz, H-2); 7.21 (d, 1H, 3J=8.5 Hz, H-7); 7.32 (dd, 1H, 4J=1.7 Hz, H-6); 7.92 (d, 1H, H-4); 11.04 (br s, 1H, NH). 13C-NMR (DMSO-D6, 75 MHz) δ 31.11 (CH2); 35.70, 37.91 (N(CH3)3); 82.82 (C-5); 108.54 (C-3); 114.51 (C-7); 125.46 (C-2); 128.16 (C-4); 129.54 (C-6); 130.85 (C-9); 135.91 (C-8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([Cl:17])[N:6]=[CH:5]2
Reactant: COc1cc(Br)cc2cnc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)cc2cnc(Cl)nc12
Temperature: 110 °C
Yield: 30 %

Procedure:
A suspension of 6-bromo-8-methoxyquinazolin-2-ol (43.96 mmol) in POCl3 (120 mL) was heated to 110° C. for 30 minutes The mixture was cooled to room temperature, evaporated POCl3 and partitioned between water and dichloromethane. The organic portion was concentrated to give a crude material which was purified by column chromatography (silica gel, eluted with 2% MeOH in dichloromethane) to yield pure material as a yellow solid in 30% yield (3 steps, 3.62 g). ES/MS m/z 272/274 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[NH:12])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N=C(Nc1cccc(NC(=O)c2ccc(Cl)cc2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 65 h

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 4-chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. A white solid developed after stirring for 65 hours, and was filtered. The filtered product was then taken up in 20 ml of isopropanol and 1 ml of concentrated hydrochloric acid was added. The mix was then brought to a volume of 500 ml with ether and crystals developed. The crystals were filtered and washed with 20 ml of ether (twice) and the product was dried in a vacuum oven, yielding N-(3-(((4-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.15 g, m.p. 247°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[C:14]([C:13]1[CH:19]=[N:4][C:3]2[C:5]([C:12]=1[OH:11])=[CH:6][CH:7]=[CH:8][C:2]=2[Br:1])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1Br
Product: CCOC(=O)c1cnc2c(Br)cccc2c1O
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) of diethyl ethoxymethylenemalonate was heated at 100° C. under a reduced pressure for 3 hours, followed by heating at 200° C. for further 12 hours. After the completion of the reaction, the solid matter in the resulting reaction mixture was washed with ethyl acetate, and the crystals were collected by filtration and dried, to give 50 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6]2)=[CH:26][CH:25]=1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (6-methylpiperidin-3-yl)carbamate (8.03 g) in dimethylformamide (90 ml) were added potassium carbonate (10.4 g) and 4-methoxybenzyl chloride (5.34 ml), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=100/3) to give the title compound (8.87 g) as a colorless oil.