Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])(=[O:20])=[O:21])[CH:18]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1 mmol) in pyridine (3 mL), 5-bromo-2-methoxybenzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with 10% aqueous HCl (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate to give 223 mg of 5-bromo-N-(4-fluoro-2-nitrophenyl)-2-methoxybenzenesulfonamide.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[C:1]([NH:9][CH:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)CNC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)C(C)C
Yield: 67.8 %

Procedure:
6.8 g of N-benzoylisobutyrylmethylamine, 1.56 g of 61% sodium hydride and 6.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(5). 6.54 g of ethyl 3-benzoylamino-3-isobutyrylpropionate are thereby obtained. Yield: 67.7%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N-methoxyethyl-methylamine (74 mg, 0.83 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 362.3 [M+H]+; tR (HPLC conditions c): 4.04 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl-].[Na+]>COCCOCCOC.O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(N2CCNCC2)c1
Reaction time: 18 h

Procedure:
A solution of 2-chloro-4,6-dimethylpyridine (30 g, 0.212 mol) in diglyme (100 mL) was added over 25-30 min. to a refluxing solution of anhydrous piperazine (147 g, 1.70 mol) in diglyme (150 mL). Heating was continued for 18 h (whereby TLC showed absence of 2-chloro-4,6-dimethylpyridine), then the mixture was cooled to room temperature and diluted with water (3 L). Sodium chloride (50 g) was added and the solution was extracted with ethyl acetate (300 mL×3); the combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo (up to 110° C. & ˜15 mmHg; to remove maximum diglyme) to afford 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (42 g, 103.3%, the G.C. spectrum showed 86.4% product, 10.7% diglyme, and 2.1% dimer.)
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and Cul (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[CH3:20][N:21]1[C:25]([CH:26]=[O:27])=[CH:24][N:23]=[CH:22]1.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]([C:25]3[N:21]([CH3:20])[CH:22]=[N:23][CH:24]=3)[OH:27])[CH:3]=2)[N:8]=1
Reactant: Cn1cncc1C=O
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cloudy mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (290.5 mg, 0.823 mmol, Intermediate 1: step c) and 1-methyl-1H-imidazole-5-carbaldehyde (90.6 mg, 0.823 mmol) in THF (8 mL) under nitrogen at −78° C. was added n-BuLi (1.6 M in hexane, 0.643 mL, 1.03 mmol) dropwise. The resulting solution was stirred at −78° C. for 3 hours, then was warmed to 0° C. for 15 minutes before addition of saturated aqueous NH4Cl to quench. The mixture was diluted with water and was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-6% MeOH-DCM) to afford the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.Cl.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH2:30][NH2:31])[N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:31][CH2:30][C:22]2[N:21]=[CH:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: NCc1cc2ccccc2cn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-isoquinolin-3-yl-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.C([Sn](Cl)(CCCC)CCCC)CCC.Cl[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[N:38]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:41]3[CH:42]=[CH:37][N:38]=[C:39]([C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)[N:40]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: Clc1ccnc(-c2ccncc2)n1
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(C)(OC)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
To a solution of 3-bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (1.0 g, 3.5 mmol) at −45° C. was added isopropylmagnesium chloride (2.6 ml of a 2M solution in THF, 5.2 mmol) dropwise. After stirring at −45° C. for 1.5 h tri-n-butylstannyl chloride (1.52 ml, 5.6 mmol) was added dropwise. The solution was stirred at −45° C. for 15 min then the cooling bath was removed and the solution stirred at room temperature for 1.5 h. After this time half of the solution was taken and degassed with N2 for 15 min. 4-Chloro-2-(pyridin-4-yl)pyrimidine (prepared according to J. Med. Chem., 1982, 25(7), 837-842) (487 mg, 2.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (294 mg, 0.26 mmol) were then added and the mixture heated at reflux for 18 h. After this time the solvent was evaporated and the residue partitioned between dichloromethane (2×40 ml) and water (40 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with 1:1 isohexane:ethyl acetate followed by dichloromethane:MeOH (97:3), to afford 7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine (171 mg, 28%) as an off-white solid: δH (360 MHz, CDCl3) 1.76 (3H, s), 3.33 (6H, s), 7.66-7.69 (2H, m), 8.28 (2H, dd, J 4.6 and 1.5), 8.60 (1H, s), 8.80-8.90 (3H, m), 10.30 (1H, d, J 7.3); m/z (ES+) 363 (M++H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C@H:13]1[CH2:41][O:40][C@@:16]2([O:20][C@H:19]3[CH2:21][C@H:22]4[C@@H:27]5[CH2:28][CH2:29][C@H:30]6[CH2:35][C@@H:34]([OH:36])[CH2:33][CH2:32][C@:31]6([CH3:37])[C@H:26]5[CH2:25][CH2:24][C@:23]4([CH3:38])[C@H:18]3[C@@H:17]2[CH3:39])[CH2:15][CH2:14]1>C(Cl)Cl.CCOCC>[CH3:39][C@@H:17]1[C@:16]2([O:40][CH2:41][C@H:13]([CH3:12])[CH2:14][CH2:15]2)[O:20][C@H:19]2[CH2:21][C@@H:22]3[C@@:23]([CH3:38])([C@@H:18]12)[CH2:24][CH2:25][C@H:26]1[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@:31]1([CH3:37])[CH2:32][CH2:33][C:34](=[O:36])[CH2:35]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
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
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Pyridinium chlorochromate (PCC) was added to a mixture of tigogenin (50.00 g, 120.0 mmol), celite (160 g), in CH2Cl2 (1000 mL) at 0° C. The reaction was allowed to come to ambient temperature and was stirred for 5 hours. The reaction was diluted with 1000 4 mL Et2O and was filtered through a silica gel plug. The plug was washed with an additional 6000 mL Et2O. The filtrate was concentrated in vacuo to afford 45.00 g of the title compound (90.4%).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.I[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36][N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[C:39]([C:48]([C:50]3[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=3)=[O:49])=[CH:38]2)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=4)[C:39]([C:48](=[O:49])[C:50]4[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=4)=[CH:38]3)=[CH:30][CH:29]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(I)cc3)c2c1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Yield: 48 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 48% yield, as a light yellow paste. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.46 (s, 9H); 1.49 (s, 3H); 3.84 (s, 6H); 3.9 (s, 3H); 3.91 (s, 3H); 4.00 (d, 2H, J=11.34 Hz); 4.1 (d, 2H, J=11.35 Hz); 5.08 (s, 2H); 5.19 (s, 1H); 6.95 (d, 1H, J=2.04 Hz); 7.00 (dd, 1H, J=2.18, 8.75 Hz); 7.11 (s, 2H); 7.3 (d, 2H, J=8.5 Hz); 7.35 (d, 2H, J=8.49 Hz); 7.74 (s, 1H); 8.25 (d, 1H, J=8.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Cl:19][CH2:20][C:21]([N:9]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: Cc1cccc(C)c1NCCCc1cccnc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)CCl
Temperature: 25 °C

Procedure:
A solution of 10.0 g of N-(2,6-dimethylphenyl)-3-pyridinepropanamine in 75 ml of dichloromethane was added dropwise to a cold (0° C.) solution of 3.5 ml of chloroacetylchloride in 35 ml of dichloromethane. The cooling bath was removed and the reaction was allowed to warm to room temperature over 30 minutes followed by the addition of excess aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and evaporated to give 13.4 g of product as a dark oil which was used directly in the next steps, that is, in Examples 20 and 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:57][O:58][C:59](=[O:78])[CH2:60][C@@H:61]([NH:69][C:70](=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=1>CN(C)C=O>[CH3:57][O:58][C:59](=[O:78])[CH2:60][C@@H:61]([NH:69][C:70](=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:62]1[CH:63]=[CH:64][C:65]([NH:68][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:66][CH:67]=1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.52 g, prepared as described in Reference Example 31) in anhydrous dimethylformamide (40 ml), under an atmosphere of argon, was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.84 g), diisopropylethylamine (3.4 ml) and a solution of (R)-3-benzoylamino-3-(4-aminophenyl)-propanoic acid methyl ester [2.0 g, Reference Example 13(a)] in dimethylformamide (10 ml). After stirring for 45 minutes at ambient temperature the reaction mixture was evaporated. The residue was treated with water (150 ml) and hydrochloric acid (10 ml, 1M) was added to the aqueous slurry. The mixture was filtered and the insoluble material was washed three times with water (50 ml) then dried in vacuo to give the title compound as white solid (2.53 g).
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17].C(Br)C#C>CN(C)C=O>[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:5]=[CH:2][C:3]=2[N:10]([CH2:11][C:16]#[CH:15])[C:9]1=[O:17]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)n(C)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
potassium tert.-butoxide, 2.1 g (18.5 mmol). was added to a solution of 2.5 g (16.9 mmol) of 1,3-dihydro-1-methyl-2H-benzimidazol-2-one in 25 ml of dimethylformamide. After stirring under nitrogen for 15 minutes, 2.21 g (18.5 mmol) of propargyl bromide was added and the mixture was stirred at room temperature for 30 minutes. It was diluted with ice-water and the precipitate was filtered off washed with water and sucked dry. The crude product was passed over silica gel using 10% (v/v) of ethyl/acetate in methylene chloride for elution. Crystallization from ethyl acetate/hexane gave colorless crystals of 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-benzimidazole-2-one with m.p. 110°-112°.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.Cl[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>O>[CH:8]1([O:12][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]#[N:21])[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCC1
Reactant: N#Cc1ccncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccncc1OC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
A mixture of mineral oil free NaH (0.86 g, 21.4 mmol) and DMF (15 ml) was cooled in an ice-bath and cyclobutanol (1.6 ml, 20.5 mmol) was added in one portion. The mixture was slowly warmed to room temperature and was stirred for 45 minutes. The mixture was once again cooled in an ice-bath and 3-chloro-4-cyanopyridine (2.6 g, 18.6 mmol) was added in one portion. The mixture was warmed to room temperature and was stirred for 3 hours. Water (10 ml) was added and the solvent was removed in vacuo. Water (225 ml) was aded to the residue and the mixture was extracted with ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4, treated with charcoal and removed in vacuo to afford 3.0 g (95%) of 3-cyclobutyloxy-4-cyanopyridine as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]3[C:23]=2[CH2:22][C:21]([CH3:24])=[CH:20]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:32][C:33]1[CH:34]([Si:54](Cl)([CH3:56])[CH3:55])[C:35]2[C:40]([CH:41]=1)=[C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:38]([O:48][CH3:49])=[C:37]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:36]=2.O>CCOCC.C([Cu])#N>[CH3:32][C:33]1[CH:34]([Si:54]([CH:20]2[C:19]3[C:23](=[C:15]([C:7]4[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=4)[CH:16]=[CH:17][C:18]=3[O:25][CH3:26])[CH:22]=[C:21]2[CH3:24])([CH3:55])[CH3:56])[C:35]2[C:40]([CH:41]=1)=[C:39]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:38]([O:48][CH3:49])=[C:37]([C:50]([CH3:51])([CH3:52])[CH3:53])[CH:36]=2
Reactant: COc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2c1C=C(C)C2
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2c1C([Si](C)(C)C1C(C)=Cc3c1cc(C(C)(C)C)c(OC)c3-c1ccccc1)C(C)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of 12.3 g (35.3 mmol) of 7-(3,5-di-tert-butylphenyl)-4-methoxy-2-methyl-1H-indene in 200 ml of ether 14.2 ml (35.5 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −50° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 150 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution of 13.6 g (35.3 mmol) of (2-methyl-4-phenyl-5-methoxy-6-tert-butyl-1H-inden-1-yl)(chloro)dimethylsilane in 200 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by dichloromethane. The combined organic elute was evaporated to dryness and dried in vacuum. This procedure gave 24.9 g of a yellowish glass. This product of ca. 90% purity was further used without an additional purification.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C]=O.O=O.[C:17]([OH:20])(=[O:19])C>>[C:17]([C:5]12[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2)([OH:20])=[O:19]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: CC(=O)O
Agent: O=O
Agent: [C]=O
Product: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Yield: 80 %

Procedure:
A reactor was charged with 10 mmole of 1,3-adamantanediol, 1 mmole of NHPI, 0.005 mmole of Co(AA)2 and 25 mL of acetic acid, then equipped with a gas bag of mixed gas (a mixed gas of 2 L of carbon monoxide and 0. 5 L of oxygen; pressure: 5 kg/cm ). The resultant mixture was stirred for 6 hours at 60° C. to give 1-carboxy-3,5-adamantanediol (yield 80%). The conversion of 1,3-adamantanediol was 99%.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:55]3[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (182 mg, 0.000272 mol) in DCM (4 mL) and 1-methylhexahydro-1H-1,4-diazepine (43.4 mg, 0.00038 mol) were mixed with sodium triacetoxyborohydride (115 mg, 0.00054 mol) and AcOH (19.5 mg, 19 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (150 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a solid. Further purification of the material was needed and this was carried out on a Chomatotron utilizing silica gel [DCM-MeOH-conc. aq. NH3, (90:7:3)] to afford 42 mg of the title compound as a glassy solid. LC-MS m/z 768.7 (M+H)+.