Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14](C)(OC3C=CC(C4NN=NN=4)=CC=3)C)[C:11]3[CH:35]=[C:36](F)[C:37](F)=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1[OH:50])[C:45]#[N:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:14][O:50][C:49]3[C:42]([F:41])=[CH:43][C:44]([C:45]#[N:46])=[CH:47][C:48]=3[F:51])[C:11]3[CH:35]=[CH:36][CH:37]=[CH:38][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)c(O)c(F)c1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 32, intermediate b), 3,5-difluoro-4-hydroxybenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless foam. MS (Turbo Spray): m/z=492.4 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:21])=[C:4]([CH3:22])[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C

Procedure:
Toluene (150 ml), 5% platinum on carbon (5.0 g), and 2-chloro-5,6-dimethyl-3-nitro-N-(2-phenoxyethyl)pyridin-4-amine (3.32 g) from Part B of Example 1 were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 4 hours with shaking. HPLC analysis indicated that the reaction was complete. The reaction mixture was filtered through a fluted filter paper and then through a folded No. 2 Whatman filter. The solvent was removed from the filtrate under reduced pressure and the resulting brown oil was used in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[C:19]([NH:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)=[O:20]>CO.ClCCl>[ClH:2].[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH:5]=1)[C:19]([NH:21][CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 196.1 %

Procedure:
Hydrochloric acid (4M in 1,4-dioxane, 3.0 ml) was added to a solution of [2-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]ethyl]carbamic acid, 1,1-dimethylethyl ester (2.2 g, Example 30b) in methanol/dichloromethane (1:1) (50 ml). After 24 h the solvent was evaporated to leave the title compound as a foam (1.85 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][CH:31]=[C:30]5[CH3:36])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:38][O:37][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:23]=[CH:22][N:21]=[C:20]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH3:36]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
7-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (5.8 g) was suspended in dichloromethane (40 ml) and cooled with an ice bath. TFA (17 ml) was added and the reaction mixture was stirred at this temperature for 1 hour. The volatiles were removed under vacuum and the residue triturated under water and dichloromethane. The pH was made basic to 12.5 with a 30% aqueous solution of sodium hydroxide while cooling with an ice bath. Extraction was done with a mixture of dichloromethane and methanol. The combined extracts were washed in turn with water and brine and dried over magnesium sulphate. The solvent was evaporated under vacuum and the residue was triturated under ether, filtered and dried to give 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quinazoline (3.6 g).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=O)[NH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([C:8]1[C:9]([SH:16])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cccc1Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Sc1ncccc1Cc1ccccc1
Reaction time: 8 h
Yield: 16.7 %

Procedure:
3-Benzyl-2-pyridone (1.65g, 8.9 mmol) and P2S5 (1.98 g, 8.9 mmol) were heated at reflux for 22 hours under argon in pyridine (17ml), and then allowed to stand overnight at ambient temperature. The mixture was diluted with brine and extracted with ethyl acetate. The ethyl acetate extracts were dried (MgSO4) and purified by chromatography using 5% CH3OH--CH2Cl2 as eluant followed by recrystallization from CH2Cl2 --ether--hexane to yield 300 mg (15%) of 3-benzyl-2-mercaptopyridine: m.p. 129°-130° C. That the 3-benzyl isomer had been isolated was confirmed by use of proton NMR spectroscopy.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C:19]6[C@@:25]([CH3:26])([C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:24][CH2:23][C:21](=[O:22])[CH:20]=6)[CH2:4][CH2:3]1.[H][H]>O1CCCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:20][C:21](=[O:22])[CH2:23][CH2:24][C@:25]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Yield: 89.6 %

Procedure:
Diosgenone (700 g) was dissolved in tetrahydrofuran (THF) (4500 ml) and inerted with nitrogen. The mixture was treated with activated carbon (35 g) and hydrogenated over 5% Pd—BaSO4 (reduced) (35 g) at 25° C. and 2.5 barg hydrogen. The catalyst was removed by filtration and the mixture concentrated to ca. quarter volume. Water (3000 ml) was added over ca. 30 minutes and the resultant solid filtered. The solid was washed with methanol (560 ml) and dried under vacuum at 40-50° C. to afford smilagenone (630 g, 90%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:23]([CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27])[CH3:24]>C1COCC1>[CH2:23]([C:25]1[C:29](=[O:30])[N:4]([CH2:1][C:2]#[CH:3])[C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:12][C:26]=1[OH:27])[CH3:24]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: C#CCNC(=N)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(O)c(CC)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a cold (-78° C.) solution of N-propargylbenzamidine (5.50 g, 34.77 mmol) in 150 mL of THF was added sodium bis(trimethylsilyl)amide (36.51 mL, 36.51 mmol, 1.05 equiv, 1M solution in THF) over 20 minutes. The reaction mixture was stirred for 5 minutes at -78° C., followed by the addidion of a cold (-78° C.) solution of ethylmalonyl dichloride (6.46 g, 38.25 mmol, 1.1 equiv.) in 150 mL of THF via a canula over 2 hours. After stirring for 30 minutes, the reaction mixture was quenched with 100 mL of water, warmed to room temperature, and diluted with 300 mL of ethyl acetate and 100 mL of water. The organic layer was successively washed with 200 mL of water and 200 mL of saturated sodium chloride, dried (MgSO4), filtered, and concentrated to give a solid. The crude mixture was azeotropically evaporated with 200 mL of toluene to remove residual hexamethyldisilazane, affording 8.28 g of 5-ethyl-6-hydroxy-2-phenyl-3-propargyl-4(3H)-pyrimidinone which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+:16]=[N-:17])[CH3:11].CC(O)(C)C>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:17]=[N:16]1)[CH3:11]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-ethynylpyridine (100 mg, 0.73 mmol) and ethylazidoacetate (0.41 ml, 0.73 mmol) were taken up in water (1.5 ml) and 2-methylpropan-2-ol (1.5 ml) at room temperature. Aqueous solutions of copper(II) sulfate pentahydrate (9.08 mg, 0.036 mmol) in 1 mL of water and L-sodium ascorbate (28.8 mg, 0.145 mmol) in 1 mL of water were sequentially added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1([C:31](=O)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CC(=O)c1ccccc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)c1ccccc1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with 1-phenylethanone (1.2 g, 10.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 75 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[C:26]3[C:38]([NH2:39])=[N:37][CH:36]=[N:35][C:27]=3[N:28]3[C:33]=2[CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]3)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:39][C:38]1[C:26]2[C:25]([C:17]3[CH:16]=[N:15][C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:33]3[N:28]([C:27]=2[N:35]=[CH:36][N:37]=1)[CH2:29][CH:30]([NH:34][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:31][CH2:32]3
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reaction time: 0.25 h

Procedure:
N,N-diisopropylethylamine (0.033 ml) and acryloyl chloride (0.0154 ml) were added to a solution of 5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine (68 mg) obtained in Step 11 in chloroform (2.5 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a yellow solid (35.4 mg).
Reaction SMILES: ClC1C=CC(S(N[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17](CCCCC2C=NC=CC=2)[CH2:18][C:19]([O:21]CC)=[O:20])(=O)=O)=CC=1>CO.[OH-].[Na+]>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCOC(=O)CC(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.7 g of ethyl 8-(p-chlorophenylsulfonamido)-3-[4-(3-pyridyl)-butyl]-octanoate, (example 14) in a mixture of 50 ml of methanol and 100 ml of 1N aqueous NaOH is stirred at room temperature for 18 h. The reaction mixture is then concentrated to remove the methanol. The product is neutralized with dilute aqueous hydrochloric acid, and the aqueous solution is extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give 8-(p-chlorophenylsulfonamido)-3-[4-(3-pyridyl)-butyl])-octanoic acid, NMR (CDCl3): delta 7.77 (d,2H), 7.43 (d,2H), 2.9 (t,2H), 2.6 (m,2H).
Reaction SMILES: I[CH:2]1[C:12](=[O:13])[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][NH:5][C:4]=2[CH2:3]1.[NH3:14]>>[NH2:14][CH:2]1[C:12](=[O:13])[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][NH:5][C:4]=2[CH2:3]1
Reactant: O=C1NC2=C(CC1I)NC=CC=C2
Reactant: N
Product: NC1CC2=C(C=CC=CN2)NC1=O

Procedure:
Thus obtained 3-iodo-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one (109 mg) was dissolved in 7 M methanolic ammonia solution (5 mL) at room temperature under argon. When the starting material was consumed, the mixture was evaporated under vacuum, and the residue was purified by silica gel chromatography to obtain 3-amino-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one.
Reaction SMILES: Br[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:7]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCC=CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.5 %

Procedure:
This example illustrates a synthesis for inventive compound no. 1591 (chemical name and structure above). To a mixture of bromohexene (10.7 g, 66 mmol, available from Aldrich) and sodium hydride (1.58 g, 66 mmol) in dimethylsulfoxide (100 mL) was added theobromine (11.9 g, 66 mmol, available from Sigma). The resulting reaction mixture was stirred for 43 hours. The reaction mixture was treated with water (200 mL) and then extracted with dichloromethane (3×80 mL). The combined extracts were washed with water (3×100 mL), dried over magnesium sulfate, and the solvent subsequently evaporated under vacuum, yielding 17 g of 1-(5-hexenyl)-3,7-dimethylxanthine (65 mmol, 98% yield) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].[CH2:34]1[CH2:38]OC[CH2:35]1.CC(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:34]([N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1)([CH3:38])[CH3:35]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A 25 mL vial was charged with a magnetic stir bar, (R or S)—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (Compound 326), THF (2.114 ml, 0.211 mmol), propan-2-one (0.061 g, 1.057 mmol), and sodium triacetoxyborohydride (0.224 g, 1.057 mmol). The reaction was allowed to stir at rt for 12 h. The reaction was inverse quenched onto sat'd aqueous NaHCO3, extracted with ethyl acetate and conc., in vacuo. The resulting material was treated with 10 mL, 7 N ammonia in MeOH and was conc in vacuo to yield material which was purified via silica gel chromatography (10 g) using DCM/MeOH/NH4OH (90:1:0.1) as eluent to afford 33 mg, (0.065 mmol, 31.0% yield) of the title compound as a white solid.). LCMS 479 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.59 (s., 1H), 7.64-7.82 (m, 2H), 7.59 (d, 1H), 6.95-7.17 (m, 2H), 6.15 (s, 1H), 4.32 (d, 2H), 4.04-4.24 (m, 1H), 3.84 (σ, 3H), 2.77-2.93 (μ, 2H), 2.68 (δ, 1H), 2.60 (σ, 3H), 2.20 (σ, 3H), 2.08-2.15 (μ, 1H), 1.92 (δ, 1H), 1.83 (βρ. σ., 1H), 1.54 (δ, 3H), 1.27-1.43 (μ, 2H), 0.91 (τ, 6H), 0.71-0.67 (μ, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(OCC)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]=[C:12]=[O:14])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 203.7 %

Procedure:
To a solution of 5-aminoindane (25 g) in anhydrous diethyl ether (1250 ml), under an atmosphere of nitrogen, at 0° C. was added triphosgene (18.3 g). The mixture was stirred at 0° C. for 2 min then triethylamine (64.7 ml) was added until pH8. The mixture was stirred at 0° C. for 10 min then at. 10° C. for 10 min. The undissolved solids were filtered off and the filtrate evaporated in vacuo. The residue was distilled at 100° C./1 mbar to afford the title compound (20 g). 1H NMR (360 MHz, CDCl3) δ2.07 (2H, quin, J=7.5 Hz), 2.86 (4H, m), 6.84 (1H, dd, J=7.9 and 2.0 Hz), 6.94 (1H, s), 7.13 (1H, d, J=7.9 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5](=[S:11])[NH:4][C:3]1=[O:12].I[CH3:14].Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([S:11][CH3:14])=[N:4][C:3]1=[O:12]
Reactant: Cn1c2c(c(=S)[nH]c1=O)CCC2
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(=O)n(C)c2c1CCC2
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
5.47 g (30 mmol) 1-methyl-2-oxo-4-thiono-1,2,3,4,6,7-hexahydro-5H-cyclopenta[d]pyrimidine was dissolved in 30 mL 1N NaOH. 2.18 mL (5.0 g, 35 mmol) iodomethane was added and the reaction allowed to continue for 30 minutes at room temperature during which the iodomethane gradually dissolved. The pH of the reaction mixture was adjusted to pH=7 with 2N HCl and then extracted 3 times with 50 mL chloroform. The collected chloroform fractions were washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue was treated with 40 mL diethylether/hexane (1:1) and 5.16 g (88%) of the intermidiate 1-methyl-4-methylthio-2-oxo-1,2,6,7-tetrahydro-5H-cyclopenta[d]pyrimidine was obtained after filtration and drying (m.p. 139–140° C., Lit. 141–142° C.).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27](O)[CH2:28]/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[I:25][CH2:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: II
Reactant: CCCC/C=C/CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC/C=C/CCI
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A mixture of Ph3P (3.205 g, 12.2 mmol), imidazole (1.221 g, 17.9 mmol), and I2 (3.024 g, 11.9 mmol) in CH2Cl2 (38 mL) was stirred at room temperature. After 15 min., a solution of 7-2 (1.283 g, 10.0 mmol) in CH2Cl2 (4.8 mL) was added by cannula, rinsing with 4 mL CH2Cl2. After 3 h, the mixture was filtered through basic alumina, washing with 10% ethyl acetate/hexanes. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (Isco Combiflash unit) to provide the title compound (2.323 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)C.CCCCCC>[Cl:19][CH2:20][C:21]([NH:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(Oc2ccc(C(=O)NC(=O)CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methoxyphenoxy)benzamide (8.34 g, 34.3 mmol) and chloroacetyl chloride (19.4 g, 171 mmol) were heated together at 100° C. for 2 hours. The cooled mixture was diluted with ethyl ether and hexane. After stirring for 1 hour at room temperature the solid was collected yielding 8.98 g of N-(2-chloroacetyl)-4-(4-methoxyphenoxy)benzmide as a light orange solid. MS (m/z, APCI): 320 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])OC(C)(C)C)=[CH:10][C:5]=2[N:4]([CH2:19][CH3:20])[CH:3]=1.ClC([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O>Cl.O1CCOCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[O:18])=[CH:10][C:5]=2[N:4]([CH2:19][CH3:20])[CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCn1cc(Br)c2cnc(NC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(Br)c2cnc(NC(=O)c3ccc(C(=O)OC)cc3)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of tert-butyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (3C, 340 mg, 0.99 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 1 h and 70° C. for 2 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml). To the mixture, methyl 4-(chlorocarbonyl)benzoate (220 mg, 1.1 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (basic-SiO2, hexanes:EtOAc=3:1) to give methyl 4-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (3D, 350 mg, 0.87 mmol, 87% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=1.00 Hz, 3H) 3.90 (s, 3H) 4.21 (q, J=7.16 Hz, 2H) 7.72 (s, 1H) 7.99-8.11 (m, 2H) 8.11-8.20 (m, 2H) 8.35 (d, J=0.76 Hz, 1H) 8.52 (d, J=1.01 Hz, 1H) 10.96 (s, 1H).