Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[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:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=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: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)on1

Procedure:
The title compound, white solid (110 mg, 97%), MS (ISP) m/z=454.4 [(M+H)+], mp 222.5° 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) (110 mg, 0.25 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:39])=[O:38]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of cholesterol (19.3 g, 50.0 mmol) in anhydrous CH2Cl2 (250 mL) was cooled to 4° C. by ice-water bath. To this solution, triethylamine (13.9 mL, 100.0 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.3 mL, 55 mmol) in anhydrous CH2Cl2 (50 mL). The reaction was maintained at 4° C. and stirred for 3 h. When the cholesterol was consumed as analyzed by TLC (hexanes/ethyl acetate, 5:1), the solvent was removed in vacuo. The resulting residue was redissolved in CH2Cl2 (15 mL), the product was precipitated by addition of MeOH (150 mL), and the product collected by vacuum filtration. The solid was washed with MeOH (30 mL) and dried under vacuum to yield the product (23.0 g, 99.0%) as a white solid, mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 5.41 (s, 1H), 4.56-4.45 (m, 1H), 3.00 (s, 3H), 2.57-2.43 (m, 2H), 2.04-0.81 (m, 38H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 123.7, 81.9, 56.5, 56.0, 49.9, 42.2, 39.6, 39.4, 39.1, 38.7, 36.8, 36.3, 36.1, 35.7, 31.8, 31.7, 28.9, 28.1, 27.9, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.6, 11.8; IR (film) ν max 3029, 2944, 2908, 2861, 1468, 1440, 1415, 1353, 1330, 1173 cm−1; ESI+ m/z ((MNa)+ 487.3237, C28H48O3SNa requires 487.3222).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH:18][C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(NNC(=O)C3CCOCC3)nc2cc1C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2nc(Cl)c3nnc(C4CCOCC4)n3c2cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 12.7 g of methyl 3-chloro-7-methyl-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate and 250 mL of tetrahydrofuran was added 5 mL of thionyl chloride, followed by stirring at 70° C. overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure and the obtained solid was washed with diethyl ether to obtain 10.4 g of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a pale yellow solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][CH:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:1]([NH:11][CH2:12][C:13]([NH:31][CH:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 4.2 g (0.02 mole) of N-carbobenzoxyglycine and 2.2 g (0.022 mole) of N-methylmorpholine in 50 ml of dry toluene was cooled to -5° and 2.8 g (0.02 mole) of isobutyl chloroformate was added thereto. After 1 hour, a solution of 3.3 g (0.02 mole) of DL-phenylalanine in 20 ml of N-sodium hydroxide was added and the mixture was stirred vigorously overnight. The aqueous phase was isolated, extracted with ether and acidified with 4 N Hydrochloric acid to precipitate the product as a colorless oil which crystallized upon cooling. Recrystallization from ethanol-water yielded 5 g (70%) of N-carbobenzoxyglycyl-DL-phenylalanine, mp 158°-160° C., RfA 0.61.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[N:4]([CH3:3])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[C:11]=1[NH2:12])=[O:16])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CNc1ccncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2cnccc2n1C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
Sodium hydride (9.0 g, 60% dispersion, 225 mmol) was suspended in DMF (150 mL) and cooled to 0-5° C. A solution of 4-methylamino-nicotinonitrile (20.0 g, 150 mmol) in DMF (100 mL) was added dropwise over ca. 20 minutes and the resulting mixture stirred cold for 30 minutes and then treated with a solution of ethyl bromoacetate (34.0 g, 225 mmol) in DMF (50 mL). The solution was allowed to warm to room temperature over 1 hour. The mixture was partitioned between ethyl acetate and water and the aqueous further extracted with ethyl acetate. The combined organic layers were washed with water (×2), brine, dried (MgSO4) and evaporated. Trituration of the resultant residue with ethyl acetate gave the title compound (12.2 g, 37%) as a yellow solid. 1H NMR (CDCl3) 1.44 (3H, t, J=7.1 Hz), 3.88 (3H, s), 4.43 (2H, q, J=7.1 Hz), 5.09 (2H, br s), 7.10 (1H, dd, 1H, J=6.1, 1.0 Hz), 8.35 (1H, d, J=6.1 Hz), 8.88 (1H, d, J=1.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[CH2:24]([N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)[CH2:27][CH2:28][OH:29])[CH3:25]
Reactant: CCNCCO
Reactant: BrCCCCCCOc1ccc2c(ccn2-c2ccccc2)c1
Product: CCN(CCO)CCCCCCOc1ccc2c(ccn2-c2ccccc2)c1

Procedure:
In analogy to example 4.4, 5-(6-Bromo-hexyloxy)-1-phenyl-1H-indole and 2-(ethylamino)ethanol were converted to yield 2-{Ethyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amino}-ethanol as colorless oil, MS: 381(MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC(C2CNc3ccccc32)CC1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-(1-acetyl-4-piperidyl)indole (48.2 g) in acetic acid (1 l) was added sodium cyanoborohydride (95 g) at 15° to 20° C. slowly over a period of 1.5 hours with stirring. The mixture was further stirred at ambient temperature for 3 hours, after which a further amount (10 g) of sodium cyanoborohydride was added. The mixture was stirred for 1 hour and the reaction mixture was diluted with water (500 ml), concentrated under reduced pressure, and allowed to stand overnight. To this reaction mixture was added 2N aqueous sodium hydroxide solution (1.5 l), and the mixture was extracted with ethyl acetate (1 l) 3 times. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was dissolved in a mixture of tetrahydrofuran (200 ml) and 2N aqueous sodium hydroxide solution (300 ml). The solution was stirred at ambient temperature for 2 hours, after which it was concentrated under reduced pressure. The residue was extracted with ethyl acetate (600 ml) and the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, elution being carried out with a mixture of chloroform and methanol (50:1 V/V) to give 3-(1-acetyl-4-piperidyl)indoline (41.1 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][NH:26]1>>[F:1][C:2]1[C:3]([C:22]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)N4Cc5ccccc5C4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and isoindoline were reacted to give the title compound. LC/MS (M+H)+: 464. Ret. time: 1.66 min. (Condition M); analytical HPLC Ret. time: 17.03 min (Condition N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:5]([C:18]([F:21])([F:20])[F:19])[CH:4]=1.N>CO.[Ni]>[NH2:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:18]([F:19])([F:20])[F:21])=[CH:17][CH:16]=1
Reactant: COc1ccc(Nc2ccc(C#N)cc2)c(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(Nc2ccc(CN)cc2)c(C(F)(F)F)c1

Procedure:
3.7 g (12.7 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile were hydrogenated in a 7N solution of ammonia in methanol (100 mL) with the addition of Raney nickel at ambient temperature. After the catalyst had been filtered off and the solvent distilled off, the crude product thus obtained was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 3-bromobenzenesulfonamide (177 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.052 g, 10%). MS (ISP) 469.4 [(M+H)+]; mp 200° C.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:28]([CH2:31][OH:32])[CH2:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:30][CH2:29][CH2:28][CH2:31][OH:32])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: NCCCO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCCO)C1(C)C

Procedure:
The product from Example 173 and propanolamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.45 (m, 3H), 1.49-1.57 (m, 2H), 1.57 (s, 9H), 1.57-1.67 (m, 3H), 1.96-2.08 (m, 1H), 2.62-2.68 (m, 3H), 2.72-2.83 (m, 1H), 2.95-3.06 (m, 1H), 3.13-3.26 (m, 1H), 3.37-3.43 (m, 2H), 4.42 (t, J=5.3 Hz, 1H), 7.56 (t, J=5.7 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 452 (M+H)+. Anal. calcd. for C24H41N3O3S: C, 63.82; H, 9.15; N, 9.30. Found: C, 63.12; H, 8.91; N, 9.25.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](OCC)(=[O:14])[C:12]#[CH:13]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:11](=[O:14])[CH:12]=[CH:13][C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: C#CC(=O)OCC
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Yield: 78.5 %

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 3-amino-5,5-dimethylcyclohex-2-en-1-one was reacted with ethyl propio-late to give the title compound as a light brown solid in 78.5% yield.
Reaction SMILES: Br[CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:27]([OH:35])(=[S:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:27]([S:34][CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(c1cccs1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 1, 1-[3-bromo-3-(2-thenoyl)propionyl]-L-proline (0.0085 mole) in 25 ml. of acetonitrile is added to a mixture of 0.015 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetontrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent removed under reduced pressure. The residue is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure to give the product of the Example as a pale yellow glass.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[CH2:12][NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:25]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[C:26]=[O:27]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[CH2:12][N:11]1[C:26](=[O:27])[NH:25][C:28]1[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(I)nn2c1CNC(CO[Si](C)(C)C(C)(C)C)C2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CN(C(=O)Nc1ccc(C#N)cc1)C(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of Intermediate 351D (1.2 g, 2.58 mmol) in THF (12 ml) was added 4-isocyanatobenzonitrile (0.446 g, 3.09 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 16% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 351E (0.6 g, 38%) as a white solid. MS(ES): m/z=610 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (s, 1H), 7.75-7.63 (m, 4H), 5.24 (d, J=18.6 Hz, 1H), 4.85-4.77 (m, 1H), 4.47 (d, J=18.6 Hz, 1H), 4.35 (d, J=2.5 Hz, 2H), 4.30-4.22 (m, 2H), 3.73-3.64 (m, 2H), 1.31 (t, J=7.0 Hz, 3H), 0.76-0.71 (m, 9H), −0.04 (m, 6H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.Cl.[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:33].[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)—N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: F[C:2]1[N:29]=[CH:28][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[N:15]=[CH:14]4)[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CS(C)=O>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:9]3[C:4]4[CH:3]=[C:2]([NH:37][CH2:36][C:35]5[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=5)[N:29]=[CH:28][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cnc(F)cc45)ccc32)c1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)ncnc3cn2)cc1
Temperature: 69 °C
Reaction time: 165 h
Yield: 60.9 %

Procedure:
A mixture of compound 202 (3.00 g, 7.73 mmol) and 4-methoxybenzylamine (10.2 mL, 77.3 mmol) in dry DMSO (18 mL) was stirred under a nitrogen atmosphere at 68-70° C. (bath temperature) for 165 h. The solution was then cooled and petroleum ether (200 mL) was added. It was stirred at room temperature for 15 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (200 ml). Water (200 mL) was added and the mixture was stirred at room temperature for 45 min. The oil was deposited. Thus, the product was extracted into ethyl acetate; dried (MgSO4) and solvent removed to give a brown oil. It was purified by a silica column (EtOAc/petroleum ether: gradient from 30% to pure EtOAc) to give pure N4-(1-(3-fluorobenzyl)-1H-indazol-5-yl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (211) (2.38 g, 61%) as a yellow/orange solid, mp 196-198° C.; 1H NMR δ [(CD3)2SO] 9.75 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.22 (poorly resolved d, J=1.3 Hz, 1H), 8.15 (d, J=0.7 Hz, 1H), 7.73 (br d, J=9.0 Hz, 1H), 7.68 (dd, J=9.0, 1.8 Hz, 1H), 7.40-7.31 (m, 3H), 7.24-7.17 (m, 2H), 7.13-7.01 (m, 3H), 6.92-6.84 (m, 2H), 5.70 (s, 2H) 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C29H24FN7O.1.5H2O: C, 65.40; H, 5.11; N, 18.41%. Found C, 65.45; H, 5.07; N, 18.58%.
Reaction SMILES: [CH2:1]([C:5]1(C)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl.[CH3:19]O>>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:19])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CO
Reactant: CC(C)CC1(C)Cc2ccccc2C=N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc2c(c1)CNC(CC(C)C)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 24.5 mg of 3-isobutyl-3-methyl-3,4-dihydroisoquinoline in methanol (1 mL) was added 4.5 mg of sodium borohydride, followed by stirring at room temperature for 5 minutes. After completion of the reaction, to the reaction liquid was added 2N hydrochloric acid, followed by drying under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 24 mg (yield 96%) of a title compound as a light yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20](Cl)=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2ccsc21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CCc2ccsc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 5,6-dihydro-4H-thieno[2,3-d]azepine-8-carboxylic acid ethyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 8.01 (1 H, s), 7.47 (1 H, m), 7.36 (1H, m), 7.27 (2H, m), 6.85 (1H, d), 4.23 (2H, q), 4.13 (2H, m), 3.15 (2H, t), 1.23 (3H, t). MS (ES): 364 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][O:30][CH2:29][CH2:28][NH:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[N:27]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH3:18])=[CH:9][CH:10]=4)[CH:5]=[N:4][N:3]=3)[CH2:28][CH2:29][O:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(C2COCCN2)cc1
Reactant: Cc1ccccc1-c1ccc2c(Cl)nncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc2c(N3CCOCC3c3ccc(Cl)cc3)nncc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of 1-chloro-6-o-tolylphthalazine (0.100 g, 0.393 mmol) in NMP (2 mL) was treated with 3-(4-chlorophenyl)morpholine (0.155 g, 0.785 mmol) and diisopropylethylamine (0.219 mL, 1.26 mmol). The reaction solution was stirred at 120° C. in a sealed tube for 16 hours. After cooling to RT, the reaction solution was treated with saturated aqueous Na2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×60 mL) and the combined organic phases were washed with brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate) gave 1-(3-(4-chlorophenyl)morpholino)-6-o-tolylphthalazine as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).