Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)cccc1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)cccc1C(=O)OCC

Procedure:
A mixture of ethyl 2-allyl-3-hydroxybenzoate (20.6 g, 100 mmol), benzyl bromide (18 g, 105 mmol), and potassium carbonate (17 g, 123 mmol), was heated in DMF to 100° C. for 18 hr. The mixture was cooled and diluted with water (500 ml), and extracted with ethyl acetate three times. The ethyl acetate extracts were dried over brine and concentrated in vacuo to a tan oil (29.6 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=1)[CH2:6][CH2:5]2.C(C1C=C(C(C)(C)C)C=CC=1OP(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:37]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([C:25]1[C:26]([Cl:29])=[C:27]([CH3:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[NH:14][S:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH2:53][C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=4)=[CH:3][CH:2]=3)(=[O:12])=[O:13])=[CH:18][C:19]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:24]=1)=[O:31])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3Br)CCN4Cc3ccc(Cl)c(Cl)c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Pd]
Agent: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)N(Cc3ccc(Cl)c(Cl)c3)CC4)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 80 °C
Yield: 54.3 %

Procedure:
To a solution of 1-(4-(5-bromo-1-(3,4-dichlorobenzyl)indolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 72, 30 mg, 0.031 mmol) in i-PrOH (4.0 mL) were added Pd2(dba)3 (23 mg, 0.025 mmol), tris(2,4-di-tert-butylphenyl)phosphite (10 mg, 0.015 mmol) and Cs2CO3 (13 mg, 0.040 mmol). The resulting reaction mixture was heated at 80° C. for 20 h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to give the title compound (15 mg, 52%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.05 (dd, J=8.4, 2.2 Hz, 1H), 7.97-7.96 (m, 1H), 7.71-7.67 (m, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.38 (dd, J=7.7, 1.5 Hz, 1H), 7.31 (dd, J=8.4, 2.0 Hz, 1H), 7.25-7.10 (m, 5.5H), 6.93 (d, J=7.5 Hz, 0.5H), 4.88-4.60 (m, 2H), 4.36 (s, 2H), 4.10-3.50 (m, 2H), 3.48 (t, J=8.5 Hz, 2H), 3.15-3.05 (m, 2H), 3.08 (t, J=8.5 Hz, 2H), 2.90-2.70 (m, 2H), 2.35 (s, 2H), 2.30 (s, 1H), 1.53-0.98 (m, 10H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.70 (t, J=7.3 Hz, 1H); MS(ESI+) m/z 891.4 (M+H)+.
Reaction SMILES: BrBr.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[N:17])[C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCCl>[NH2:15][C:13]1[S:14][C:10]2[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=2[C:12]=1[C:16]#[N:17]
Reactant: N#CC(C(N)=S)c1ccc([N+](=O)[O-])cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1c(N)sc2cc([N+](=O)[O-])ccc12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of 1.3 ml (25 mmol) of bromine in 10 ml of dichloroethane is added dropwise to a suspension of 5.53 g (25 mmol) of p-nitrophenylcyanothioacetamide and 4.2 g (50 mmol) of sodium hydrogencarbonate in 40 ml of 1,2-dichloroethane. The temperature is maintained at 20° C. by cooling with ice-water. This is followed by 30 minutes of stirring, filtering off with suction and washing with water. Drying in vacuo at 50° C. leaves 4.9 g of a brown powder=89% of theory.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])C.C(Br)C.[C-:21]#[N:22].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH3:17][O:16][C:14]([C:6]1[NH:7][C:8]2[C:13]([C:5]=1[CH2:4][C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:15]
Reactant: COC(=O)c1[nH]c2ccccc2c1CN(C)C
Reactant: [C-]#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCBr
Product: COC(=O)c1[nH]c2ccccc2c1CC#N
Reaction time: 0.17 h

Procedure:
40.6 g Product from (b) were dissolved in 300 ml DMSO and 14.5 ml ethylbromide were added. After 10 minutes, 11.4 g KCN were added and the mixture was stirred for 48 hours. The reaction mixture was poured into citric acid and extracted with CH2Cl2. The solvent was evaporated to give 26 g yellow residue.
Reaction SMILES: [F:1][CH:2]([F:24])[CH:3]([NH:16]C(OC(C)(C)C)=O)[CH2:4][C:5](=[CH2:15])[CH2:6][NH:7]C(OC(C)(C)C)=O.[ClH:25]>CCOCC>[ClH:25].[ClH:25].[F:1][CH:2]([F:24])[CH:3]([NH2:16])[CH2:4][C:5](=[CH2:15])[CH2:6][NH2:7]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(NC(=O)OC(C)(C)C)C(F)F
Agent: Cl
Solvent: CCOCC
Product: C=C(CN)CC(N)C(F)F
Reaction time: 8 h

Procedure:
1,1-Difluoro-2,5-di-t-butoxycarbonylamino-4-methylene-pentane (3.3 g, 9.4 mmoles) is dissolved in dry ether saturated with hydrogen chloride gas. After standing overnight, the hygroscopic solid obtained is recrystallized twice from methanol/methylene chloride (1.49 g, 71%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C(OOC(C)(C)C)(=O)C(C)(C)C.ClC1C=CC=CC=1>[C:12]1([C:3]2=[CH:2][C:1]([O:6][C:4]2=[O:5])=[O:7])[CH2:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Agent: CC(C)(C)OOC(=O)C(C)(C)C
Solvent: Clc1ccccc1
Product: O=C1C=C(C2=CC=CC2)C(=O)O1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
The copolymerization of 1.2 g (12 mmoles) of maleic anhydride with 0.8 g. (12 mmoles) of cyclopentadiene using 0.3 ml. (1 mmole) of t-butyl peroxypivalate as catalyst at 80° C. was carried out in the presence of 1.8 ml. of chlorobenzene, using the procedure described in Example VI. The catalyst addition was carried out over a period of 10 min. and the reaction mixture was then maintained at 80° C. for an additional 50 min. The 1:2 cyclopentadiene-maleic anhydride copolymer was obtained in a yield of 0.64 g. (40%)
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[C:20]([NH:19][CH2:18][CH2:17][C:14]1[C:13]2[CH:23]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11][C:12]=2[O:16][CH:15]=1)(=[O:22])[CH3:21]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)NCCc1coc2ccc(C=O)cc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at room temperature to a solution of 6.88 mmol of the product obtained in Step D in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed over silica gel to yield the title product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1ccc(C(=O)OC)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Methyl 3-cyano-4-ethyl-benzoate (D45) (1.92 g) was dissolved in MeOH (50 mL) before adding 1M NaOH solution (15.24 mL) and stirring the resulting mixture overnight at room temperature, under argon. The reaction mixture was diluted with water, and extracted with EtOAc. The aqueous layer was acidified to pH1 using 2M HCl before extracting with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and the solvent evaporated to dryness in vacuo to afford the title compound (1.63 g). 1H NMR (CDCl3) δ 1.35 (3H, t), 2.97 (2H, q), 7.49 (1H, d), 8.24 (1H, dd), 8.36 (1H, d).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.O>CO>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)c(OC)c1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 4,6-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, water 400 ml was added, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.95 g.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[CH:13][CH:12]=1)[CH2:2]2.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9](=[O:22])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[N:20][N:19]=[N:18]4)=[CH:15][CH:16]=2)[CH2:4]3)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (100 mg, 0.335 mmol) was combined with 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.34 mmol) and Hunig's base (43.3 mg, 0.335 mmol) in acetonitrile (1 mL) and stirred at 60° C. for 5 h. Purification by mass-directed HPLC afforded the title compound. LC/MS: [(M+1)]+=448.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23](=O)[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].[OH-].[Na+]>CO>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH2:33])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)N)ccc2-3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanone (0.126 g, 0.000342 mol) in methanol (5.0 mL) was added ammonium acetate (0.140 g, 0.00182 mol) then sodium cyanoborohydride (0.172 g, 0.00274 mol). The reaction was stirred at 50° C. overnight. The mixture was basified with 1N NaOH and extracted 3 times with methylene chloride. The organic phases were combined, dried with Na2SO4 and concentrated to give 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]ethylamine. MS (ESI+) 370.2.
Reaction SMILES: [O-]S([O-])=O.[Na+:5].[Na+].[O:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:22]([C:24]2[CH:25]=[C:26]([S:37](Cl)(=[O:39])=[O:38])[CH:27]=[CH:28][C:29]=2[O:30][C@@H:31]([CH3:36])[C:32]([F:35])([F:34])[F:33])=[O:23])[CH2:16]3)[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>O>[Na+:5].[O:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:22]([C:24]2[CH:25]=[C:26]([S:37]([O-:39])=[O:38])[CH:27]=[CH:28][C:29]=2[O:30][C@@H:31]([CH3:36])[C:32]([F:34])([F:35])[F:33])=[O:23])[CH2:16]3)[CH2:9][CH2:8]1
Reactant: C[C@H](Oc1ccc(S(=O)(=O)Cl)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[C@H](Oc1ccc(S(=O)[O-])cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
1.15 g (8.94 mmol) of Na2SO3 and 1.70 g (9.60 mmol) of Na2HPO4 hydrate were dissolved in 13 ml water. An ethanolic solution of 2.40 g (4.63 mmol) of 3-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carbonyl]-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl chloride was added. The reaction mixture was stirred at 35 to 40° C. during 1 hour and then overnight at room temperature. 1.3 g Speedex was added, the reaction mixture was filtered and the filtrate was evaporated. The crude product was treated with aqueous citric acid/NaCl solution then extracted with MTBE/THF 1:1. The organic solvent was evaporated and the residue was dissolved in MeOH/water (2:1), and treated with 800 mg (9.52 mmol) of NaHCO3. 1 g Speedex was added and the reaction mixture was filtrated and concentrated in vacuo. The residue was purified chromatographically by using a reverse phase column (RP-18, water/methanol) to provide 1.12 g (48%) of the title compound as a white foam. MS (m/e): 484.3 [M+H]+.
Reaction SMILES: BrCCBr.Cl[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
96 g (4 moles) of Mg turnings in 60 ml of absolute tetrahydrofuran (THF) are initially taken under a nitrogen atmosphere. 1 ml of 1,2-dibromoethane is added at 65° C., after which a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 1 of absolute THF is added dropwise in the course of 21/4 hours. Thereafter, the mixture is stirred for 4 hours under reflux and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF are added under nitrogen. When the reaction is complete, the Grignard reaction mixture is worked up in an aqueous medium in a conventional manner and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30°-107° C./0.27 mbar). The remaining crude product (676 g), which contains as much as 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be further purified by column chromatography using toluene as the mobile phase.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19]C1C=CC=CC=1)[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:29])=O>>[Cl:29][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 90 %

Procedure:
Dimethylformamide (0.2 ml) was added dropwise to a solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-one (5.00 g, 17.9 mmol) in thionyl chloride (100 ml) and the reaction was heated at reflux for 1 hour. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (3×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (4.80 g, 90% yield) as a pale brown solid:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-methoxybenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 435 (M+NH4)H. 1H-NMR (DMSO-d6) δ 3.21-3.26 (m, 1H), 3.37-3.46 (m, 3H), 3.63-3.68 (m, 2H), 3.70 (s, 3H), 4.02 (s, 2H), 4.53 (t, J=5.4 Hz, 1H), 5.09 (d. J=5.3 Hz, 1H), 5.15 (d. J=5.0 Hz, 1H), 5.20 (d, J=5.9 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.2, 7.9 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 7.07 (td, J=8.0, 5.2 Hz, 1H), 7.17 (d, J=8.7 Hz, 2H), 7.19 (s, 1H), 7.35 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N+:11]=[N-:12]>>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:13]([N:10]=[N+:11]=[N-:12])[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)CN=[N+]=[N-]
Product: COC(=O)C(=Cc1ccccc1C)N=[N+]=[N-]

Procedure:
Following the general procedure of PREPARATION 61 and making non-critical variations but starting with o-tolualdehyde (5.0 g), methyl azidoacetate (19.2 g), the title compound is obtained, NMR (300 MHz, CDCl3) 7.96, 7.26-7.18, 7.13, 3.92 and 2.36 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:16]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[NH2:16]
Reactant: COc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N2CCN(C)CC2)cc1N
Yield: 90.4 %

Procedure:
A solution of 1-(4-methoxy-3-nitro-phenyl)-4-methyl-piperazine (1.0 g, 4.0 mmol) in MeOH (100 mL) in the presence of Pd/C 10% (150 mg) was hydrogenated at 35 psi for 2 h. The mixture was filtered over a pad of celite and the solution was concentrated to afford 0.8 g (90% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1.C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)=[CH:32][N:31]=2)[CH2:3][CH2:4][CH:5]([N:8]([CH3:44])[C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:10]2)[CH2:6][CH2:7]1
Reactant: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4cnccn4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCC(O)(c2ccc(-c3cnccn3)cn2)CC1)[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
N-[2-((3S)-3-{[4-Hydroxy-4-(5-pyrazin-2-ylpyridin-2-yl)cyclohexyl]amino}pyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl)benzamide (29.0 mg, 0.051 mmol) and 37% aqueous formaldehyde (21 uL, 0.26 mmol) were dissolved in THF (1.0 mL). The mixture was evaporated to dryness. Then the residue was taken up in THF (1 mL) and sodium triacetoxyborohydride (24 mg, 0.11 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to provide the title compound (5.9 mg). MS (M+H) 583.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11](OS(C(F)(F)F)(=O)=O)[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH:11]=[CH2:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)OS(=O)(=O)C(F)(F)F)CCCCO1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: ClCCl
Product: C=CC1(C(=O)OC)CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A solution of 2-(1-trifluoromethanesulfonyloxy-ethyl)-tetrahydro-pyran-2-carboxylic acid methyl ester (2.12 g, 3.3 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen. 1,8-Diazabicycloundec-7-ene (2.0 g, 2 mL, 13.2 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was cooled to 0° C. and acidified to pH 2 with ice cold hydrochloric acid (2 M). The mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford the title compound (466 mg, 75% over two steps) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.55-1.80 (m, 5H), 2.21-2.29 (m, 1H), 2.68-2.77 (m, 1H), 3.79 (s, 3H), 3.91-3.98 (m, 1H), 5.26 (dd, J=10.7, 0.9 Hz, 1H), 5.41 (dd, J=17.4, 1.1 Hz, 1H), 5.87 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 193.2 [M+H], Tr=2.01 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)CC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Fc1ccc(Cl)nc1
Solvent: CCCO
Solvent: O
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Yield: 122.1 %

Procedure:
A mixture of 2-chloro-5-fluropyridine (5 g, 0.038 mol) and hydrazine monohydrate (15 ml, 0.32 mol) in n-propanol (40 ml) in a teflon container was purged with argon and heated in a stainless steel bomb at 200° C. for 19 h (magnetic stirring). Evaporation of solvent and excess hydrazine monohydrate in vacuo gave a solid residue (5.9 g) which was dissolved in sodium bicarbonate solution (5%) and extracted with 6×50 ml ethyl acetate. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give an oil (2.9 g) which proved difficult to purify and was therefore used as such in the next step. The crude product consisted of a ternary mixture of the desired product, 2-chloro-5-hydrazinopyridine, and 5-hydrazinopyridine.