Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH:9]=[C:8]([C:11]3[C:15]4[CH:16]=[N:17][C:18]([NH2:32])=[C:19]([O:20][C@@H:21]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=5[Cl:31])[CH3:22])[C:14]=4[O:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.C[Si]([N:37]=[C:38]=[O:39])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C.N>CO>[NH2:32][C:18]1[N:17]=[CH:16][C:15]2[C:11]([C:8]3[CH2:7][CH2:6][N:5]([CH:3]4[CH2:2][N:1]([C:38]([NH2:37])=[O:39])[CH2:4]4)[CH2:10][CH:9]=3)=[CH:12][O:13][C:14]=2[C:19]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CNC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CN(C(N)=O)C4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-Azetidin-3-yl-1,2,3,6-tetrahydropyridin-4-yl)-7-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0209 mmol), trimethylsilyl isocyanate (4.25 μL, 0.0314 mmol), DMF (1.0 mL, 13 mmol) and DIPEA (7.30 μL, 0.0419 mmol) were mixed together and stirred at room temperature for 1 hour. The crude was passed through SCX-2 SPE and the product was release by 2 M NH3 in methanol for MDP purification. MS (ES+): m/z 555.05/557.04 (100/76) [MH+]. HPLC: tR=0.55 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=6.8 Hz, 3H), 2.56 (br. s., 2H), 2.67-2.73 (m, 2H), 3.15-3.22 (m, 2H), 3.34-3.42 (m, 1H), 3.89 (dd, J=8.6, 5.3 Hz, 2H), 4.01-4.09 (m, 2H), 6.27 (br. s., 1H), 6.50 (q, J=6.7 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[N:13]=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:10]=[C:9]([C:12]3[N:13]=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[CH:8]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)[nH]n3)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)OC(C)(C)C)n3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]-1-(4-methoxybenzyl)-1H-1,2,3-triazole (19.0 g, 0.052 mol) in anhydrous THF (100 mL) was added NaH (2.6 g, 0.06 mol) at 0° C. and the mixture was stirred at RT for 2 hours. tert-butyl bromoacetate (12.5 g, 0.057 mol) was then added at 0° C. and the mixture was stirred at RT for 2 hours. The mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:1) to yield the title compound (20.0 g, 76.0%) as a yellow solid.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][SH:31].Cl>[OH-].[Na+].C1COCC1>[C:1]([NH:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][SH:31])(=[O:12])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/C(=O)N[C@@H](CS)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a THF (20 ml) solution containing geranic acid (1.68 g, 10 mmols), triethylamine (1.01 g, 10 mmols) was added and cooled to 0° C., into which a THF (5 ml) solution of isobutyl chloroformate (1.37 g, 10 mmols) was added dropwise, followed by 30 minutes' stirring at 0° C. To the reaction mixture a solution of cysteine (1.35 g, 10 mmols) as dissolved in 1N sodium hydroxide (10 ml) was added, followed by an hour's stirring at 0° C. and further 4 hours' stirring at room temperature. After termination of the reaction, 10 ml of 1N hydrochloric acid was added to the reaction mixture and stirred for 10 minutes at room temperature. Then the reaction mixture was condensed with a rotary evaporator. To the residue ethanol was added, and whereupon precipitated sodium chloride was removed by filtration. The ethanol solution was once again condensed under reduced pressure with the evaporator, and the residue was separated on silica gel column chromatography. Thus 0.556 g of the title compound was obtained from the hexane-acetone (2:1) distillate. The yield was 19.5%:
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:29][CH2:30][NH2:31]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (0.490 g, 0.94 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 h. Sodium hydroxide (2 M, 30 mL) was added and the mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (90:5:5 CH2Cl2—CH3OH—NH4OH) provided 294 mg (97%) of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine as a colorless oil. 1H NMR (CDCl3) δ 1.60-1.75 (m, 1 H), 1.87-1.98 (m, 1 H), 2.01 (m, 1 H), 2.22 (m, 1 H), 2.56-2.85 (m, 6 H), 4.03 (m, 1 H), 4.04 (d, J=16.8 Hz, 1 H), 4.17 (d, J=16.8 Hz, 1 H), 7.11-7.21 (m, 3 H), 7.40 (d, J=7.8 Hz, 1 H), 7.56 (brs, 2 H), 8.55 (d, J=4.2 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:4]=[C:5]([CH3:7])[N:6]=1.[N+:16]([O-])([OH:18])=[O:17].C(=O)(O)[O-].[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1cn(-c2ccccc2C#N)c(C)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc(C)n(-c2ccccc2C#N)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Compound 6 (6.82 grams, 34.5 mmol) was added in portions to trifluoroacetic anhydride (50 mL) cooled to 0° C. After 15 minutes the sodium chloride ice water bath was replaced with a dry ice acetone bath and nitric acid (6.0 mL 70%) was added drop wise. This was stirred to ambient temperature for 16 hours after which time it was pored into ice-water and neutralized with solid sodium bicarbonate. The product was extracted with dichloromethane and purified on a silica gel flash column eluted with 49:1 dichloromethane-methanol to give the desired product as an orange paste. LCMS data supported the structure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24](=O)[NH:25][CH:26]([C:35]#[N:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24]3[NH:25][C:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[C:35]([Cl:49])[N:36]=3)[N:23]=[C:12]21)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(Cc1ccc(F)cc1)NC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(NC12CCC(CC1)Cn1c2nc(-c2nc(Cl)c(Cc3ccc(F)cc3)[nH]2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-((1-cyano-2-(4-fluorophenyl)ethyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 5 (140 mg, 0.220 mmol) in acetonitrile (4 mL) was added carbon tetrachloride (0.053 mL, 0.551 mmol), followed by triphenylphosphine (144 mg, 0.551 mmol) and the mixture was heated at 45° C. After stirring for 16 h, the mixture was cooled to room temp and concentrated in vacuo. The residue was then treated with dichloromethane (10 mL) and 0.5 N NaOH (20 mL). The mixture was then poured into water and extracted with dichloromethane (×4), dried (Na2SO4), filtered and concentrated. The crude product was then purified by silica gel chromatography (40-100% EtOAc/hexane) to afford the title compound (90 mg, 42% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.65-1.74 (m, 2H) 1.92-2.03 (m, 4H) 2.47 (br. s., 1H) 2.71-2.86 (m, 2H) 3.74 (s, 2H) 4.13 (d, J=3.66 Hz, 2H) 5.12 (s, 2H) 5.29 (s, 2H) 6.92 (d, J=7.63 Hz, 4H) 7.08 (br. s., 1H) 7.29-7.37 (m, 8H) 7.39-7.46 (m, 2H) 10.08 (br. s., 1H). (M+H)=654.28.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH3:37])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: CC(N)CO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(CO)NC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 40 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 2-amino-1-propanol as for example 34. After workup, the residue was triturated with hexane, then dried to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxy-1-methylethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (40%) as a cream solid; m.p. (EtOAc/Hexane) 198-202° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.10 (br s, 1H), 8.26 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.72 (dd, J=10.2, 1.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.58 (s, 1H), 4.73 (t, J=5.8 Hz, 1H), 3.97 (p, J=6.7 Hz, 1H), 3.47-3.39 (m, 1H), 3.38 (s, 3H), 3.37-3.33 (m, 1H), 1.12 (d, J=6.7 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0383. HPLC 95.1% (254 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.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>[CH3:24][O:23][C:19](=[O:22])[CH:20]=[CH:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(C2=CCCCc3ccccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C2=CCCCc3ccccc32)cc1
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To a solution of 9-(4-bromophenyl)-6,7-dihydro-5H-benzocycloheptene (2a, compound III, R3=H, X=Br, n=2) (12.38 g, 41 mmol) in DMF (30 mL) was added methyl acrylate (38.2 g, 444 mmol), triethylamine (29.0 g, 286 mmol), and bis(triphenylphosphine)palladium(II) chloride (7.0 g, 10.0 mmol). The mixture was placed in a pressure bottle and heated at 100° C. for 4 days. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester (2b) as a white solid (11.4 g, 90%): 1H NMR (CDCl3) δ 7.69 (d, J=15.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.24 (m, 5H), 6.98 (m, 1H), 6.52 (t, J=7.3 Hz, 1H), 6.43 (d, J=15.7 Hz, 1H), 3.81 (s, 3H), 2.65 (t, J=7.0 Hz, 2H), 2.17 (m, 2H), 1.98 (m, 2H); APcI m/z: 346 (M+H+CH3CN+, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:12]I.[OH-].[K+]>CN(C=O)C>[I:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Reaction time: 4 h

Procedure:
To a solution of 1H-indazole-5-carboxaldehyde (670.2 mg, 4.59 mmol) in DMF (5 mL) were added iodine (2.33 g, 9.17 mmol) and potassium hydroxide pellets (1.03 g, 18.36 mmol) at room temperature under stirring. After 4 h, the mixture was quenched with aqueous Na2S2O3 solution and extracted with EtOAc. The combined extracts were washed with brine, dried, and evaporated to afford the title product.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]N(C)C=O.[K].IC>O.CC(O)(C)C>[C:1]1([CH:7]([CH3:16])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CI
Product: CC(C(=O)c1cccnc1)c1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirred and cooled (0° C.) solution of 70 parts of 2-phenyl-1-(3-pyridinyl)ethanone in 225 parts of N,N-dimethylformamide were added dropwise 46.9 parts of 2-methyl-2-propanol, potassium salt under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at 0° C. The reaction mixture was allowed to reach room temperature and 70 parts of iodomethane were added. The reaction mixture was allowed to stand at room temperature for 8 hours. The mixture was poured into water and the product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated to dry, yielding 30 parts (40%) of 2-phenyl-1-(3-pyridinyl)-1-propanone as a residue (intermediate 8).
Reaction SMILES: [OH:1][C@@H:2]([CH2:32][CH3:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[ClH:34]>ClCCl>[ClH:34].[CH3:24][NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:32][CH3:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1
Reactant: CC[C@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-hydroxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (110 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (7 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give (2S)-1-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol hydrochloride (90 mg, crude), which was used in the next step directly without further purification. The hydrochloride salt thus obtained (90 mg) was dissolved in methanol (8 mL). Then HCHO (37%, 1 mL) was added and the mixture was stirred at room temperature for 1 h. This was followed by the addition of NaBH3CN (41 mg, 0.65 mmol, 2.99 equiv). The resulting solution was stirred overnight at room temperature and quenched by the addition of water. The mixture was extracted with 3×10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Waters): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.05% NH4HCO3) and CH3CN (7.0% CH3CN up to 60.0% in 14 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 48.4 mg (57%) of (2S)-1-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol as a light yellow semi-solid. MS (ES): m/z 390 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.46 (1H, s), 5.26-5.31 (1H, m), 3.61-3.63 (2H, m), 3.05-3.15 (1H, m), 2.95-3.00 (1H, m), 2.60-2.71 (1H, m), 2.25-2.50 (10H, m), 2.10-2.20 (1H, m), 2.00-2.08 (2H, m), 1.65-1.75 (2H, m), 1.40-1.52 (5H, m), 0.97 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH2:15])=[O:13]
Reactant: CN1CCOCC1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)cc2ccccc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of 1-methylindole-2-carboxylic acid (5.0 g, 28.5 mmole) in THF (100 mL) at 0° C. was added N-methylmorpholine (3.5 mL, 31.8 mmole) followed by isobutyl chloroformate (4.0 mL, 30.8 mmole) dropwise over 5 minutes. A thick slurry formed quickly. The mixture was stirred for 30 min, then conc. NH4OH (4.0 mL. 58 mmole) was added in one portion with vigorous stirring, and the cooling bath was removed. The reaction was stirred at RT for 4 hr then was concentrated to dryness. The residue was triturated with 1.0 N Na2CO3 (50 mL), filtered, washed with a small volume of cold water, and dried under vacuum to give the title compound (2.46 g, 50%) as a white solid: Silica gel TLC (5% MeOH/CHCl3) Rf0.50.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C(O)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
2-(4-Methoxy-phenyl)-trans-cyclopropanecarboxylic acid ethyl ester (1.43 g, 6.51 mmol) is dissolved in dry dichloromethane (30 mL) and cooled to −78° C. Boron tribromide solution (1 M in dichloromethane, 7.81 mL, 7.81 mmol) is added dropwise then the mixture is allowed to warm to −20° C. and stirred overnight at −20° C. Ethanol (3 mL) is added and the mixture warmed to room temperature then diluted with saturated aqueous sodium bicarbonate solution. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried through a phase seperator and the solvent removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) and then crystallised from 10% ethyl acetate in cyclohexane to give the title compound (yield 0.58 g).
Reaction SMILES: [CH:1](=[C:3]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][CH2:4]1)[CH3:2].C1(C(=CC(=CC=1)C)C)C>[Pd]>[CH2:1]([C:3]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][CH:4]=1)[CH3:2]
Reactant: CC=C1CCCC(C)(C)C1=O
Agent: [Pd]
Agent: Cc1ccc(C)c(C)c1
Product: CCC1=CCCC(C)(C)C1=O
Temperature: 170 °C
Yield: 94.9 %

Procedure:
5% Palladium on carbon (11 g), 6-ethylidene-2,2-dimethylcyclohexan-1-one (415 g) and pseudocumene (390 g) were charged in a reactor. The reactor was purged with N2 gas. The reaction mixture was heated to 170° C. and acid formic (3 g) was added over 15 h. The reactor was cool down. The reaction mixture was filtrated and distilled under reduced pressure afforded 2-ethyl-6,6-dimethylcyclohex-2-en-1-one (394 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Li+].[B-](CC)(CC)CC.O>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CO)cc1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of 16.0 g (76.6 mmole) of dimethyl aminoterephthalate in 200 ml of anhydrous THF cooled to −78° C. is added 250 ml (250 mmole) of 1 M Super Hydride dropwise over 1 hour. The mixture is stirred for an additional 1.5 hours warming to 0° C. (a little starting material on TLC is observed). The mixture is poured into 300 ml of cold water and extracted with ethyl acetate. The organic layer is washed with water and the two layers are allowed to stand for 30 minutes. The organic layer is dried over MgSO4 and filtered. The filtrate is evaporated. The residue is dissolved in ethyl acetate and the solution is poured over a Buchner funnel containing silica gel, using 150 ml of ethyl acetate to wash the funnel. The filtrate is evaporated. The residue is dissolved in the minimum amount of ethyl acetate and the solution is diluted to the cloudy point with hexane. Additional hexane is added as the product precipitates. A total of 100 ml of hexane is added and the solid is collected and vacuum dried to give 8.4 g of the title intermediate material, 98-100° C. mp; 61% yield. 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, 1H), 6.67 (s, 1H), 6.60 (d, 1H), 5.75 (bs, 2H), 4.62 (s, 2H), 3.86 (s, 3H), 1.83 (bs, 1H). EI MS, [M]+=181.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C=CC#N
Solvent: CO
Product: COc1ccc(CCNCCC#N)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
54.5 gm of 2-(3,4-dimethoxy-phenyl)-ethylamine were dissolved in 100 ml of methanol, a solution of 16.2 gm of acrylonitrile in 50 ml of methanol was added dropwise at 50°C, and the mixture was stirred for 1 hour at 50°C. After evaporation of the methanol, the raw reaction oriduct thus obtained was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].Cl.[NH2:31][OH:32]>C(O)C>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:17]([NH:31][OH:32])=[NH:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: NO
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=N)NO)(c2ccc(Cl)cc2)CC1

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile (0.1 mmol, 1.00 eq), 24 mg hydroxylamine hydrochloride (0.33 mmol, 3.00 eq), 94uL TEA (0.66 mmol, 6.00 eq), and 500uL ethanol. The mixture was heated to 55C overnight and the solvent removed in vacuo. The crude material was used “as is” in the following step: