Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:37][C:38]1[C:39]([N:46]2[C:50]3=[N:51][CH:52]=[N:53][C:54](Cl)=[C:49]3[CH:48]=[N:47]2)=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:54]1[N:53]=[CH:52][N:51]=[C:50]2[N:46]([C:39]3[C:40]([C:41]#[N:42])=[CH:43][CH:44]=[CH:45][C:38]=3[Cl:37])[N:47]=[CH:48][C:49]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
60% Sodium hydride (95 mg, 2.38 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (540 mg, 1.08 mmol) in anhydrous THF (15 mL), at 0° C., under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (314 mg, 1.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and was then stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane. Fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (466 mg, 57.2%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, d), 3.83-3.66 (4H, m), 4.11-4.04 (1H, m), 4.20-4.12 (1H, m), 6.00 (1H, s), 7.44-7.31 (6H, m), 7.60 (4H, m), 7.87 (2H, m), 8.03 (1H, t), 8.22-8.13 (2H, m), 8.39 (1H, d), 8.62 (1H, d), 8.68 (1H, d), 11.23 (1H, s). m/z (ES+) (M+H)+=752; HPLC tR=3.89 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:7][CH2:6][N:5]1[CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[N:5]([CH3:19])[CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH2:16])[CH2:9]1
Reactant: [H][H]
Reactant: COCC1CN(c2ccncc2[N+](=O)[O-])CCN1C
Agent: [Pd]
Solvent: CO
Product: COCC1CN(c2ccncc2N)CCN1C

Procedure:
To a solution of 2-(methoxymethyl)-1-methyl-4-(3-nitropyridin-4-yl)piperazine (84 mg, 0.3.1 mmol) in methanol was added Pd on C (10%, wet, Degussa) (10 mg) and the reaction mixture was stirred overnight at room temperature under a balloon of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield 4-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-amine as a film. (72 mg, 96%). MS (ES+) 267.1.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.[CH3:20][C:21]([O:24][C:25]([NH:27][C@:28]([CH3:40])([CH2:38][CH3:39])[C:29](=[O:37])SC1C=CC=CN=1)=[O:26])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:40][C@:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])([C:29]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:2]([CH3:1])[CH2:3][CH2:4][O:5]3)=[N:14][CH:15]=1)=[O:37])[CH2:38][CH3:39]
Reactant: CC1CCOc2cccc(Oc3ncc(N)cn3)c21
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Sc1ccccn1
Solvent: Cc1ccccc1
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
2-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-pyrimidinamine (Intermediate 217, 144 mg, 0.56 mmol) was dissolved in toluene (8.0 mL) and S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 86 mg, 0.28 mmol) was added. The reaction mixture was stirred at 140° C. for 20 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 134 mg, 0.43 mmol) was added and the mixture was stirred at 140° C. for 15 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 50° C. overnight and at 80° C. and for 4 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 80° C. for 20 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 50 mg, 0.16 mmol) was added and the reaction mixture was stirred for additional 30 hours at 80° C. After cooling volatiles were removed and the residue was purified by flash chromatography (Biotage SP1) on silica gel using a 10 g SNAP silica cartridge as column and cyclohexane/ethyl acetate from 10:0 to 1:1 as eluents affording the title compound (100 mg).
Reaction SMILES: N12CCCCC1C=NCCC2.[CH:12]1([C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[NH:18][N:17]([N:24](C3C=CC=CC=3)[C:25](=[O:27])[O-])[N:16]=2)[CH2:14][CH2:13]1.[F:34][CH:35]([F:47])[O:36][C:37]1[C:38]([S:43]([NH2:46])(=[O:45])=[O:44])=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[F:47][CH:35]([F:34])[O:36][C:37]1[C:38]([S:43]([NH:46][C:25]([NH:24][N:17]2[N:16]=[C:15]([CH:12]3[CH2:13][CH2:14]3)[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[NH:18]2)=[O:27])(=[O:44])=[O:45])=[N:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC1=CC(C2CC2)=NN(N(C(=O)[O-])c2ccccc2)N1
Reactant: NS(=O)(=O)c1ncccc1OC(F)F
Agent: C1=NCCCN2CCCCC12
Solvent: CC#N
Product: CCOC1=CC(C2CC2)=NN(NC(=O)NS(=O)(=O)c2ncccc2OC(F)F)N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
1.63 ml of 1,5-diazabicyclo(5.4.0)undec-5-ene followed by 3.15 g of N-(4-cyclopropyl-6-ethoxy-triazin-2-yl)-phenylcarbamate are added to a solution of 2.24 g of 3-difluoromethoxypyridin-2-yl-sulfonamide in 40 ml of acetonitrile. The reaction mixture is stirred for 45 minutes at room temperature and then concentrated using a rotary evaporator. The oily residue is triturated with 8 ml of 2N hydrochloric acid and diluted with 10 ml of water. The crystal mass is filtered off, washed with water and diethyl ether and dried, yielding 4.05 g of N-(3-difluoromethoxypyridine-2-sulfonyl)-N'-(4-cyclopropyl-6-ethoxy-triazin-2-yl)-urea having a melting point of 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1>C1COCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])(=[O:18])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenyl)1,1-dioxidothiomorpholine (4.00 g, 14.58 mmol) in THF (50 mL) was added Pd/C (1.30 g). The reaction mixture was stirred at rt under H2 for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as an offwhite solid (2.40 g, 67%).
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][CH:2]1[C:3](=[O:5])[C:18]2[C:17](=[CH:26][CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)[N:16]=[C:8]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)C(C)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)C(C)C(c1ccccc1)=N2
Yield: 28.1 %

Procedure:
Ethyl alpha-methylbenzoylacetate (5 grams) and 3.67 grams of methyl p-aminobenzoate are dehydrated (by heating) for three days in 100 ml of chloroform in the presence of 0.7 gram of p-toluenesulfonic acid. p-Toluenesulfonic acid is removed therefrom, the filtrate is concentrated, and purified by silica gel column chromatography to give an oil. The resulting oily product is heated to reflux in 70 ml of diphenyl ether, cooled, and crystals which separate therefrom are collected by filtration and recrystallized from a mixture of dimethyl formamide and water to give 2 grams of methyl 3-methyl-2-phenyl-4-quinolone-6-carboxylate, colorless crystals, melting point above 300° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:32])=[O:3])=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2c(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cccc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2c(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cccc21

Procedure:
In analogy to the procedure described for example 1 e], {4-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH:5]([N+:11]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C.[H][H]>>[NH2:11][CH:5]([CH:4]([O:14][CH2:15][CH3:16])[O:3][CH2:1][CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(OCC)OCC)[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(N)C(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl 3,3-diethoxy-2-nitropropanoate (2.45 g, 10.42 mmol) was dissolved in Ethanol (70 mL, 1240 mmol). Nitrogen gas was bubbled through the mixture for 5 minutes. Raney® nickel was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 13 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was removed from the apparatus and filtered over celite. Filter cake was washed with 150 mL ethanol followed by 250 mL hot ethanol. Filtrate was concentrated to dryness. Title compound was obtained as red oil in 92% yield. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 4.59 (d, J=4.39 Hz, 1 H) 4.05-4.30 (m, 2 H) 3.65-3.81 (m, 2 H) 3.38-3.63 (m, 3 H) 1.87 (s, 2 H) 1.20-1.29 (m, 3 H) 1.12-1.20 (m, 6 H).
Reaction SMILES: [CH3:1]/[C:2](/[CH:27]=[CH:28]/[CH:29]=[C:30](/[CH:32]=[C:33]=[C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][C@H:37]([OH:42])[CH2:36][C@:35]1(O)[CH3:43])\[CH3:31])=[CH:3]\[CH:4]=[CH:5]\[CH:6]=[C:7](\[CH:9]=[CH:10]\[CH:11]=[C:12](/[CH:14]1O[C@:17]2([CH3:26])[CH2:19][C@@H:20]([OH:25])[CH2:21][C:22]([CH3:24])([CH3:23])[C:16]2=[CH:15]1)\[CH3:13])/[CH3:8].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C=C\C=C(\C=C\C1C(C)(C)CCCC=1C)/C)/C.C/C(/C=C/C=C(/C=C/[C@]12C(C)(C)C[C@H](O)C[C@@]1(C)O2)\C)=C\C=C\C=C(\C=C\C=C(\C=C=C1C(C)(C)C[C@H](O)C[C@]1(O)C)/C)/C.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(/C=C/C=C(/C=C/C=C(/C(O)=O)\C)\C)\C.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(/C=C/C=C(/C=C/C=C(/C(OC)=O)\C)\C)\C.CC(C)=CCC/C(/C)=C/CC/C(/C)=C/C=C/C(/C)=C/C=C/C=C(/C=C/C=C(/C=C/C=C(/CCC=C(C)C)\C)\C)\C.CC1[C@H](/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(/C=C/C=C(/C=C/C=C(/CCC=C(C)C)\C)\C)\C)C(C)(C)C(C/C=C(/CO)\C)CC=1.C/C(/C=C/C=C(\C)/C=C/C(O)=O)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C(O)=O.CC1C[C@@H](O)[C@H](O)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1C(C)(C)[C@@H](O)[C@H](O)CC=1C>>[CH3:26][C:17]1[C@H:16](/[CH:15]=[CH:14]/[C:12](/[CH3:13])=[CH:11]/[CH:10]=[CH:9]/[C:7](/[CH3:8])=[CH:6]/[CH:5]=[CH:4]/[CH:3]=[C:2](\[CH3:1])/[CH:27]=[CH:28]/[CH:29]=[C:30](\[CH3:31])/[CH:32]=[CH:33]/[C@H:34]2[C:35]([CH3:43])=[CH:36][C@H:37]([OH:42])[CH2:38][C:39]2([CH3:41])[CH3:40])[C:22]([CH3:24])([CH3:23])[CH2:21][C@@H:20]([OH:25])[CH:19]=1
Reactant: C/C(=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(\C)C=C=C1C(C)(C)C[C@H](O)C[C@@]1(C)O)C1C=C2C(C)(C)C[C@H](O)C[C@@]2(C)O1
Agent: C/C(C=C=C1C(C)(C)C[C@H](O)C[C@@]1(C)O)=C\C=C\C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C
Agent: CC(/C=C/C=C(C)/C=C/C(=O)O)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C(=O)O
Agent: CC(C)=CCC/C(C)=C/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/[C@H]1C(C)=CCC(C/C=C(\C)CO)C1(C)C
Product: CC1=C[C@H](O)CC(C)(C)[C@H]1/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/[C@H]1C(C)=C[C@H](O)CC1(C)C

Procedure:
Neocarotene; Neochrome; Neo-β-carotene B; Neo-β-cryptoxanthin A; Neoxanthin; Neoxanthin 3-acetate; Neurosporaxanthin; Neurosporaxanthin methyl ester; Neurosporene; Nonaprenoxanthin; 2′-Nor-astaxanthin diester; Norbixin; Nostoxanthin;
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1(Cl)[NH:12][C:11]([Cl:13])=[CH:10][S:9]1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:15][NH2:16]>>[CH:1]([N:4]([NH:16][CH3:15])[S:5]([C:8]1[S:9][CH:10]=[C:11]([Cl:13])[N:12]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reactant: CN
Product: CNN(C(C)C)S(=O)(=O)c1nc(Cl)cs1
Yield: 78 %

Procedure:
In analogy to Example 5, the N-isopropyl-2-N-methylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-isopropyl-2,4-dichlorothiazole-sulphonamide from Example 3 with 30% strength aqueous methylamine solution. Following recrystallization from toluene, the product of m.p. 187°-8° C. was obtained in a yield of 78% of the theoretical yield.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)#[N:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:8][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:2]
Reactant: COc1ccc(C=O)cc1OCC#N
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN2CCCC2)cc1OCC#N
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of 3-cyanomethoxy-4-methoxybenzaldehyde (10.0 g) in 1,2-dichloroethane (400 ml) was added pyrrolidine (6.6 ml), with stirring, followed by sodium triacetoxyborohydride (22 g). The reaction mixture was stirred at ambient temperature for 1 hr and poured into ice/water 10% sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and high performance liquid chromatographed, eluting with dichloromethane, 1%, 2% and 5% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 8.7 g (63.5%) of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1)[C:5]([NH2:7])=[O:6].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:17]=1)[C:5]([NH2:7])=[O:6]
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2)c(Cl)c1
Yield: 96.9 %

Procedure:
Use 3-chloro-4-(4-formyl-phenoxy)-benzamide (0.20 g, 0.71 mmol), 2-thiophen-2-yl-ethylamine (0.075 mL, 0.64 mmol), sodium borohydride (0.049 g, 1.29 mmol) and methanol (8 mL) in a procedure and purification similar to that of Example 1, to obtain the product (0.24 g, 94%), serial number 2137632. Mass spectrum (ion spray): m/z=387.1 (M+1); 1H NMR (CDCl3) 7.93 (d, J=2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.14 (d, J=5.2 Hz, 1H), 6.97 (d, J=8.3 Hz, 2H), 6.93 (dd, J=3.4 Hz, 5.1 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.1 Hz, 1H), 6.11 (bs, 2H), 3.81 (s, 2H), 3.05 (t, J=6.7 Hz, 2H), 2.95 (t, J=6.7 Hz, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=1[CH3:36]>CN(C=O)C>[C:38]([NH:37][C:32]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:30]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)[CH:31]=1)(=[O:42])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 62 %

Procedure:
To a 50-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (500 mg, 1.62 mmol), K2CO3 (670 mg, 4.86 mmol) and PdCl2dppf (0.190 mmol, 155 mg) was added a solution of N-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×20 mL). The filtrates were washed with H2O (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (360 mg, 62%): ESMS m/e: 303.0 (M-56+H)+.
Reaction SMILES: NC1C=C(OC)C(C)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([CH3:51])[C:47]([O:49][CH3:50])=[CH:48][C:43]=2[N:42]=[C:41]2[N:52](CC=C)[NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([CH3:51])[C:47]([O:49][CH3:50])=[CH:48][C:43]=2[N:42]=[C:41]2[NH:52][NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1C
Product: COc1cc2c(cc1C)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3,7-dimethyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVz) was prepared by reacting 0.0012 moles of (2-amino-4-methoxy-5-methylphenyl)-(2-chlorophenyl)-methanone (Xz) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3,7-dimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVz) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=353.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Reactant: NC(=O)C1CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(NC(=O)C3CC3)cn2)CC1
Temperature: 110 °C
Yield: 55.1 %

Procedure:
A mixture of 0.20 g (0.56 mmol) of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester, 22 mg (0.12 mmol) of CuI, 0.035 mL (0.22 mmol) of 1,2-trans-di(methylamino)cychlohexane, 0.090 mg (1.1 mmol) of cyclopropanecarboxamide, and 0.24 mg (1.1 mmol) of K3PO4 in 1 mL of 1,4-dioxane was heated under an N2 atmosphere for overnight at 110° C. The mixture was cooled, diluted with 10 mL of EtOAc, and washed with aq. NH4Cl/NH4OH (pH 8), then with aq. NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was triturated with acetonitrile to provide 98 mg (56%) of {1-[5-(cyclopropanecarbonyl-amino)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester as an off-white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:14]=[N:15][N:16]=[CH:17]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCCn2cnnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCn2cnnc2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
4-[3-(4-nitrophenyl)propyl]-4H-1,2,4-triazole (1.2 g) was dissolved in ethanol (100 ml), 10% palladium-activated carbon (50% hydration, 0.2 g) was added to the solution at room temperature, and the solution was reduced by catalytic hydrogenation overnight. The catalyst was removed. The solvent of the filtrate was distilled off, to give 4-[3-(4-aminophenyl)propyl]-4H-1,2,4-triazole (1.0 g) as colorless crystals.
Reaction SMILES: N1C=CC=CC=1S[S:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].C(S)[C@@H](O)[C@H](O)CS.CCN(CC)CC>CO>[SH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: O=C(NCCSSc1ccccn1)c1ccc[cH-]1
Agent: [Fe+2]
Agent: O[C@H](CS)[C@H](O)CS
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCCS)c1ccc[cH-]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 12 (113 mg, 0.28 mmol) dissolved in 6 mL of MeOH was added DTT (438 mg, 2.8 mmol) and Et3N (79 mL, 0.57 mmol). The solution was stirred at room temperature for 18 h, followed by evaporation of the solvent. The residue was dissolved in 15 mL of EtOAc and rinsed with H20 (8×15 mL) to remove excess DTT. After drying over MgSO4 and concentrating, the residue was purified by flash chromatography (hexanes/EtOAc, 1:1, v/v) to afford 46 mg (57%) of 13. 1H NMR 400 MHz (CDCl3) d 6.16 (br s, 1H), 4.66 (t, J=1.8 Hz, 2H), 4.33 (t, J=1.8 Hz, 2H), 4.19 (s, 5H), 3.53 (q, J=6.4 Hz, 2H), 2.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:32]=[O:33])C>C1COCC1>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:32]([OH:33])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccc(Cl)c(Cl)c2C1O
Yield: 83 %

Procedure:
In a similar manner to Step 2 of Example 16, 3,4-dichloro-N-(1-methyl-1-phenylethyl)benzamide (2.85 g, 9.25 mmol) was dissolved in THF (114 mL), and the solution was treated with TMEDA (4.50 mL, 29.6 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 29.3 mL, 29.6 mmol) and DMF (1.60 mL, 20.4 mmol), followed by purification by slurry using diisopropylether to obtain 4,5-dichloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.58 g, yield 83%).