Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[ClH:5].Cl.[CH2:7]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.Cl>[ClH:5].[CH2:7]([C:14]1[CH:15]=[C:16]([NH:17][C:2]([NH2:3])=[O:1])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)NCCCOc1ccc(N)cc1Cc1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)NCCCOc1ccc(NC(N)=O)cc1Cc1ccccc1
Reaction time: 2 h
Yield: 283.9 %

Procedure:
Potassium cyanate (44 mg) was added to a stirred solution of 3-benzyl-4-(3-[N-isopropylamino]propoxy)aniline dihydrochloride (222 mg) in water (5 mls). The reaction mixture was stirred for 2 hours and the resulting precipitate collected by filtration. The solid collected was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 90:10:1 (v/v/v) mixture of dichloromethane/ethanol/ammonia (density=0.88 g/cm3) as eluent to give a residue which was dissolved in saturated methanolic hydrogen chloride solution. The solution was evaporated to give a solid which was crystallised from ethanol to give 3-benzyl-4-(3-[N-isopropylamino]propoxy)phenylurea hydrochloride as a white solid (582 mg), m.p. 204.7° C., microanalysis, found: C, 63.6; H, 7.6; N, 10.9%; C20H23N3O. HCl requires: C, 63.6; H, 7.47; N, 11.1%; NMR:([CD3 ]2SO): 1.2(6H,d), 2.05(2H,m), 2.9(2H,t), 3.25(1H,m), 3.85(2H,s), 4.0(2H,t), 5.7(2H,s), 6.82(1H,d), 7.05-7.3(7H,m), 8.4(1H,s), 7.5(2H,s); m/z 342(M+H).
Reaction SMILES: [CH:1]1([C:4]([CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[O:5])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:15]1[O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:4]([CH:1]3[CH2:2][CH2:3]3)[OH:5])=[CH:9][C:10]=2[O:16]1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC(CCc1ccc2c(c1)OCO2)C1CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 18.4 g. of 2-(3,4-methylenedioxyphenyl)vinyl cyclopropyl ketone (Preparation A2) and 3.1 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 11.5 g., b.p. 116°-122° C. (0.005 mm.), m.p. 64°-65° C. when recrystallized from ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH3:22])[C:10]=2[CH:23]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:25][O:24][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:10]2[C:11]([CH3:22])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(-c3ccccc3)c(C)c2cc1OCCCCl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(-c3ccccc3)c(C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 66 %

Procedure:
Method B (40 h at 50° C.); starting materials: 6-(3-chloropropoxy)-7-methoxy-4-methyl-3-phenyl-2H-1-benzopyran-2-one (example 79) and 1-phenylpiperazine; yield 66%; fusion point 168°-170° C. (from isopropanol). Fumarate: method E; yield 95%; fusion point 219°-221° C. (from acetone).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=CC(=O)N1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Maleimide (20.0 g, 206 mmol) and trityl chloride (57.4 g, 206 mmol) were mixed together in 200 ml of chloroform and triethylamine (31.3, 309 mmol) was added dropwise to the reaction over a period of 20 minutes. After stirring for one hour at room temperature, the reaction was washed with 10% aqueous hydrogen chloride (HCl) solution and dried over magnesium sulfate (MgSO4). The crude product was slurried in 20 ml of ethylacetate. A total of 18.4 g of a solid material was filtered and dried (60% yield). 1H NMR (CDCl3): 7.31 (m, 15H, aromatics), 6.25 (s, 2H, vinyl).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:15][CH:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[O:25][CH3:26])[CH2:13]1)=[O:11].[BH4-].[Na+]>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([CH:12]1[CH2:15][CH:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[O:25][CH3:26])[CH2:13]1)[OH:11]
Reactant: COc1nc2cccnc2n1C1CC(C(=O)c2nc3ccccc3[nH]2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2cccnc2n1C1CC(C(O)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C

Procedure:
(1H-benzo[d]imidazol-2-yl)(3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)methanone (60 mg, 0.17 mmol) was dissolved in dry tetrahydrofuran (10 mL) and treated with sodium borohydride (11 mg, 0.29 mmol). The reaction was stirred at room temperature until the starting material was consumed by TLC. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, followed by prep. TLC (dichloromethane:methanol=10:1) to give two isomers of (1H-benzo[d]imidazol-2-yl)-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)methanol as mixtures of diastereomers. M+1: 367.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:17][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (3.99 g, 20 mmol) in THF (40 mL) were added ethylamine (20 mL of a 2.0 M solution in THF, 40 mmol), acetic acid (1.15 mL, 20 mmol) and sodium triacetoxyborohydride (8.48 g, 40 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 1 N aqueous sodium hydroxide (120 mL) at 0° C. and stirred at room temperature for 30 minutes. The organic solvent was evaporated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate (40 mL, 2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the title compound (4.54 g, 19.9 mmol, 99%) as a pale yellow oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:18][CH:17]3[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:16]3[CH2:15]2)=[O:13])[NH:4][CH:5]=1.FC1C=CC=C(N2N=CC=N2)C=1C(N1CC2C(CN(C3N=C(C)N=CN=3)C2)C1)=O>>[N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:15][CH:16]3[CH:17]([CH2:19][NH:20][CH2:21]3)[CH2:18]2)=[O:13])[NH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: Cc1ncnc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CNCC2C1

Procedure:
(2-(4H-1,2,4-Triazol-3-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone was prepared in a manner analogous to Example 303, substituting Intermediate 59 for the product of Example 303 in Step C. MS (ESI) mass calculated for C15H17NO, 283.14; m/z found, 284.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7](=[O:14])[CH2:6][C:5]2([CH3:16])[CH3:15].CC(C)=[O:20].O.C1C(=O)N(Br)C(=O)C1>C(#N)C>[CH3:15][C:5]([C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:17])([CH3:16])[CH2:6][C:7]([OH:20])=[O:14]
Reactant: Cc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Reactant: CC(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Yield: 96 %

Procedure:
To the solution of 6-hydroxy-4,4,5,7,8-pentamethylchroman-2-one (15 g, 0.064 mol) in a mixture of acetonitrile (600 ml), acetone (50 ml) and water (300 ml), NBS (11.4 g, 0.064 mol) was added. The resultant mixture was stirred for 30 minutes at room temperature. After removing most of the organic solvent, the yellow solid was collected by filtration, washed by water and dried over vacuum to afford a yield of 96%. 1H NMR (300 MHz, CD2Cl2) δ 3.0 (s, 2H, CH2), 2.13 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.92 (s, 3H, CH3), 1.44 (s, 6H, CH3); MS (m/e): 251 (M+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:19][C:20]#[N:21])[CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[C:20]=2[NH2:21])[CH:18]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(Cl)cc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(Cl)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.9 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (1.04 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.388 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.820 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.480 g, 28% yield). M.p. 153.5-154.7° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=S.CCN(C(C)C)C(C)C>C(#N)C>[OH:7][CH2:6][C@H:2]([NH:1][C:9]1[S:8][CH2:14][C:12](=[O:13])[N:11]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@H](CO)NC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 48 h
Yield: 41.8 %

Procedure:
To a suspension of (R)-valinol (1 g, 9.69 mmol) and Rhodanine (1.3 g, 9.69 mmol) in acetonitrile (40 mL) was added DIPEA (5.06 mL, 29 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (2.72 g, 10 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The filtrate was removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.82 g (42% yield) of 2-(1-(R)-hydroxymethyl-2-methylpropylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C8H14N2O2S (M+) 202.0776. found 202.0778.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>>[F:1][C:2]([F:22])([F:23])[CH2:3][N:4]([C:5]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8])[C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC(F)(F)F
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC(F)(F)F)C(=O)C(Cl)(Cl)Cl

Procedure:
A mixture of 3.24 g of 2-(2,2,2-trifluoroethylamino)-5-nitrobenzophenone and 15 ml. of trichloroacetyl chloride was heated at 100° C. (bath temperature) for 5 hours. The volatiles were removed under reduced pressure. The residue was chromatographed on silica gel using benzene as an eluent to give 2-[N-(2,2,2-trifluoroethyl)trichloroacetamido]-5-nitrobenzophenone as an yellow oil.
Reaction SMILES: [Br:1]Br.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][C@H:11]1[CH3:26])=[O:9])([CH3:6])([CH3:5])[CH3:4]>ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][C:19]([Br:1])=[CH:18][N:17]=2)[CH2:12][C@H:11]1[CH3:26])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: BrBr
Solvent: ClCCl
Product: C[C@@H]1CN(c2ncc(Br)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Bromine (1.52 mL, 29.7 mmol, Aldrich) was added dropwise over a period of 5 min to a solution (2R)-2-methyl-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (9.34 g, 27 mmol) in dichloromethane (100 mL) with stirring at room temperature. The mixture was stirred at room temperature for 30 min, the solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The solution was washed with sat. NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound as a gum. MS (ESI, pos. ion) m/e: 426 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:21])[CH2:9]1)=[O:7])(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:26]=[CH:27]C(O)=O>>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10](=[O:21])[CH2:9]2)=[O:7])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCN(CCN2CCCC2)C(=O)C1

Procedure:
The title compound was prepared in analogy to example 6 starting from 3-oxo-4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 6) and 3,4-dichlorocinnamic acid. MS (ISP)=396.4 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][NH:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=O>C1COCC1>[CH3:7][NH:8][CH2:9][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CNC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2[nH]1
Reaction time: 23 h
Yield: 510.9 %

Procedure:
A solution of LiAlH4 in THF (1.0 M, 250 mL, 250 mmole) was slowly added via syringe to a solution of N-methyl-1H-indol-2-carboxamide (21.50 g, 12.34 mmole) in anhydrous THF (100 mL). Gas was evolved during the addition of the first 50 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (9.5 mL). 1.0 N NaOH (20 mL), and H2O (28.5 mL). The mixture was stirred for 15 min. then was filtered through Celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% cone. NH4OH). The title compound (10.10 g, 51%) was obtained as a light yellow oil: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)=[O:4].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[CH:33]1([NH:39][CH2:2][C:3]([NH:5][C:6]2[CH:24]=[CH:23][C:9]([C:10]([N:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)=[O:4])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCCCC1
Reactant: O=C(CCl)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CNC1CCCCC1)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 1-[4-(2-chloroacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.06 g) in dimethylformamide (5 ml) are added sodium iodide (0.90 g), potassium carbonate (1.1 g) and cyclohexylamine (0.89 g), and the mixture is stirred at room temperature for 2 hours. Dimethylformamide is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-[4-(2-cyclohexylaminoacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.03 g) as white powder, m.p. 139°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH2:18][NH:17][CH2:16][CH2:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:26][C:25]1[C:20]([N:17]2[CH2:16][CH2:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:10]=3[CH2:18]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccnc1Cl
Reactant: Fc1ccc(Nc2ncnc3c2CNCC3)cc1
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.47 g, 1.92 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (420 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (200 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15](/[CH:17]=[CH:1]/[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:16]
Reactant: Cc1ccncc1[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=C/c1ccncc1[N+](=O)[O-]

Procedure:
Commercially available 4-methyl-3-nitropyridine is condensed with N,N-dimethylformamide diethyl acetal to provide E-4-[2-(N,N-dimethylamino)-1-ethenyl]-3-nitropyridine, which is then subjected to catalytic hydrogenation to give 6-azaindole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O[Li].O.Cl>C1COCC1.CO.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:12][C@@H:13]([C:26]([OH:28])=[O:27])[N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:15]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:36])([F:38])[F:37])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.50 g, 1.94 mmol, See Ex. 1u) in THF (20 mL), MeOH (10 mL) and water (10 mL) was added LiOH—H2O (0.80 g, 19.4 mmol), and the reaction was stirred at RT for 4 h. The pH of the reaction mixture was adjusted to 6.5 with 6 N HCl, and the organic solvents were removed in vacuo to provide a white solid that is filtered away. The reaction mixture was then partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, then concentrated in vacuo to provide (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid that is used directly without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[CH:15][C:14]([NH:22][CH3:23])=[CH:13][C:12]2=1)C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[CH3:23][NH:22][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:18][C:19]1[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][C:11]2=1
Reactant: CNc1ccc2[nH]c3ccc(OCc4ccccc4)cc3c2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1ccc2[nH]c3ccc(O)cc3c2c1
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
A mixture of 6-(benzyloxy)-N-methyl-9H-carbazol-3-amine 4 (93 mg, 0.31 mmol), Pd/C (10 mg) and acetic acid (10 drops) in MeOH (10 mL) was hydrogenated at room temperature for 1.5 hrs. It was passed through a short Celite pad. The filtrate was concentrated in vacuo to give the desired product 5 (66 mg). It was used directly in the next step without any further purification. MS: m/z=213 (M+H+)+.