Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.CCN(CC)CC>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2nnnc2-c2ccc(Br)cc2)cc1

Procedure:
At room temperature, to a stirred mixture of 5-(4-bromophenyl)-1H-tetrazole (2.15 g, 9.55 mmol) in CH3CN, add 4-methoxybenzyl chloride (1.42 mL, 10.50 mmol) followed by Et3N (1.46 mL, 10.50 mmol) and stir over night. Concentrate the mixture to half the volume and add water (100 mL). Filter the white precipitate and wash with water (100 mL). Dry the material to give 5-(4-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole as white flocculent crystals (1.37 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].[CH3:17][O:18]CCN1C=C(Br)C=N1>>[CH3:17][O:18][CH2:2][CH2:1][N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[N:4]1
Reactant: COCCn1cc(Br)cn1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, using 1-(2-methoxyethyl)-4-bromo-1H-pyrazole (see Ivachtchenko, A. V., et al J. Het. Chem. 2004, 41, 931-939).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[CH2:16]([C@@H:23]([CH2:34][OH:35])[C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1F)[OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH2:16]([C@@H:23]1[C@@H:24]([OH:25])[C:26]2[C:31](=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[O:35][CH2:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to a solution of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. The mixture was slowly heated to 60° C. under aspirator vacuum to displace the tetrahydrofuran from the reaction mixture, and then heated at 60 to 65° C for 5 hours under aspirator vacuum at which point the reaction was judged to be complete according to thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambient temperature and quenched by adding water (10 L) followed by 1N aqueous hydrochloric acid (10 L). The resulting tan suspension was filtered, washed with water (2 L), and dissolved in ethyl acetate (12 L). This solution was washed with water (two times 12 L), concentrated to a low volume, dissolved in isopropyl ether (4 L), and concentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids began to precipitate. The resulting suspension was cooled to ambient temperature, stirred for 12 hours, concentrated to one-half its volume, cooled to 0 to 5° C., and filtered giving 916 g (49%) of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L) at reflux, cooled to ambient temperature, stirred, and filtered yielding an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich fractions were concentrated and recrystallized from isopropyl ether yielding an additional 82 g of solid. The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs,1H), 4.21 (dd, J =2.6, 11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd, J=6.5, 13.8 Hz, 1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3 Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1673, 1493, 1480, 1410. 1219, 1070, 1052, 1023, 859, 700 cm-1 ; mp 143.5-144.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20]C(OC(C)(C)C)=O)[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH2:20])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (0.23 g, 0.54 mmol) in DCM (3 mL) at rt was added TFA (1 mL). After 2 h, the mixture was concentrated, diluted with water, and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated to provide 100 mg (57%) of the amine as a tan viscous oil. MS (ESI+): mass calcd. for C16H15Cl2NO2, 323.05; m/z found, 324 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32-7.19 (m, 8H), 4.26 (d, J=8.0, 1H), 4.15 (app q, J=7.4, 1H), 3.57 (s, 3H), 1.46 (br d, J=6.6, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH2:24][Br:46]
Reactant: COCCOCOc1c(C/C=C(\C)CO)c(OC)c(C)c2c1C(=O)OC2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To a solution of (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-en-1-ol (4.6 g) in methylene chloride (100 ml) at 0° C. was added triphenylphosphine (3.64 g) then N-bromosuccinimide (2.48 g). After 15 minutes the solution was washed with 10% aqueous sodium bisulphite, water, aqueous sodium bicarbonate, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 4:1 hexane: ethyl acetate, to give (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-enyl bromide, mp 74°-75° C. (hexane).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[Br:11][C:12]1[CH:13]=[C:14]([O:21][CH3:22])[C:15]2[N:16]([N:18]=[CH:19][CH:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([O:21][CH3:22])[C:15]2[N:16]([N:18]=[CH:19][C:20]=2[CH:9]=[O:10])[CH:17]=1
Reactant: COc1cc(Br)cn2nccc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)cn2ncc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (513 μl, 5.51 mmol) was added to DMF (8.52 ml, 110 mmol) at 0° C. The bath was removed and the solution was allowed the solution to warm to ambient temperature. After 30 minutes, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.202 mmol) was added, and the mixture was allowed to stir at ambient temperature. After 3.5 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL) and stirred for 60 minutes. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The solid was placed under vacuum overnight to remove excess DMF and afford 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde contaminated with about 9% of the starting material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:26])=O>>[NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:26])=[O:8]
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reaction time: 1.5 h
Yield: 69 %

Procedure:
The flask was charged with thionyl chloride (600 ml, 978.6 g, 8.23 mol) and 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoic acid (320 g, 0.56 mol) was added in portions with stirring. The mixture was refluxed for one hour and an additional 100 ml of thionyl chloride was added. Refluxing was continued for 1.5 hours (total reflux time: 2.5 hours) until TLC indicated that the reaction was complete. Thionyl chloride was removed by vacuum distillation (30° C., 75 mmHg) until the consistency of the residue was pasty. The remaining traces of thionyl chloride were removed by three consecutive vacuum codistillations with 200 ml of THF. The resulting yellow paste was dissolved in 600 ml of THF and immersed in an ice bath while 500 ml of saturated NaCl was added. The pH of the aqueous layer (<1) was adjusted to approximately 6.9 with solid sodium carbonate (173 g, 1.63 mol). The mixture was filtered and the filter cake was washed with 200 ml of THF. The wash was combined with the mother liquor which was then allowed to separate into two layers. The organic layer was washed with 200 ml of saturated NaCl, the aqueous layer with 150 ml THF; the organic layers were combined and dried over 180 g of calcium chloride beads for one hour. The solution was concentrated to a volume of 400 ml and stirred with 200 ml of dry toluene for 16 hours. The creamy white solid thus formed was filtered, washed with 2×100 ml of dry cold toluene and dried under vacuum to give 228 g of product 2 (0.39 mol, 69% ) as a pale yellow solid. 13C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 170.2, 150.4, 148.9, 148.7, 83.0, 75.3, 70.1, 25.8. TLC: One spot (EtOAc/MeOH/HOAc, 10/5/1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccc(C)c(C=O)c1
Product: Cc1ccc(C)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5-dimethyl-benzaldehyde. MS (ESI) m/z 497.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O>>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: OO
Reactant: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Yield: 40.2 %

Procedure:
2-Methylthio-3-nitro-4-n-butylpyrrole (3.7 g) was suspended in glacial acid (50 ml) and 30% hydrogen peroxide (1.62 g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-n-butylpyrrole (1.6 g), m.p. 133°-4°.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (which may be prepared as described above; 44.5 mg, 0.1 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (12 mg) as a yellow solid. LCMS analysis indicated that the purity of this material was 42%. MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH:9]=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>ClCCl>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][CH:2]([CH2:8][CH:9]=[C:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:36])=[O:35])=[CH:32][CH:33]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(N)CC=C1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC=C1CCOCC1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-amino-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (163) (1.0 g, 4.7 mmol) in anhydrous dichloromethane (30 mL) was added Hunig's base (1.6 mL, 9.4 mmol) followed by 4-nitrobenzenesulfonyl chloride (1.14 g, 5.2 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was diluted with dichloromethane and washed with 0.1 N HCl, the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-70% hexanes/EtOAc to afford the title compound as an off-white solid in quantitative yield.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].C(O[C@@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[O:15][CH3:16])(=O)C.O1CCOCC1>P([O-])([O-])([O-])=O>[C:1]([S:3][C@H:10]1[NH:13][C:12](=[O:14])[C@@H:11]1[O:15][CH3:16])(=[O:4])[CH3:2]
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Reactant: CC([O-])=S
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 equivalents of an aqueous sodium thioacetate solution are added to a solution of 40 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine (for manufacture see below) in 1.5 ml of phosphate buffer of a pH of 7 and 0.1 ml of dioxan, and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is extracted with methylene chloride and the separated organic solution is then dried over sodium sulphate. The solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel with toluene/ethyl acetate (3:1). The IR spectrum of the resulting title compound (in methylene chloride) is identical to that of the product obtained according to a).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29](O)=[O:30])[N:14]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:30])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)O)c4c3)n2)c2ccccc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)N5CCOCC5)c4c3)n2)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of the carboxylic acid described above (460 mg, 80% pure, 0.90 mmol) in THF (6.0 mL) at RT was added HATU (613 mg, 1.61 mmol) and DIPEA (0.340 μL, 1.97 mmol). After 10 min the resulting mixture was treated with morpholine (0.141 mL, 1.61 mmol) and after a further 16 hr at RT additional portions of HATU (170 mg, 0.45 mmol), DIPEA (80 μL, 0.45 mmol) and morpholine (39 μL, 0.45 mmol) were added. The resulting mixture was maintained at RT for a further 24 hr and was then partitioned between saturated aq. NaHCO3 (20 mL) and EtOAc (20 mL). The organic phase was separated and was washed sequentially with 1M hydrochloric acid (20 mL), water (2×30 mL) and brine (2×30 mL) and was then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-100% [10% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound, Intermediate B18, as a dark purple solid (165 mg, 82% pure, 24%); Rt 1.55 min (Method 2, acidic); m/z 482 (M+H)+ (ES+). The material was used in subsequent reactions without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([OH:35])[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:49][O:48][C:46]([N:33]1[CH2:34][C:31]([C:28]2[CH:29]=[CH:30][C:25]([N:9]3[C:10](=[O:24])[CH2:11][C:12]4[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)[C@@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][CH:27]=2)([OH:35])[CH2:32]1)=[O:47]
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CC(O)(c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of (S)-1-(4-chloro-phenyl)-2-[4-(3-hydroxy-azetidin-3-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one (example 56) (40 mg, 0.081 mmol) in DCM (2 ml) was immersed in an ice-bath. DIPEA (Fluka) (0.043 ml, 0.243 mmol) was added, followed by methyl chloroformate (Fluka) (8.17 μl, 0.105 mmol). Afterwards the reaction was stirred in an ice-bath for 30 min. The reaction mixture was taken up in aqueous NaHCO3 solution. The organic phase was extracted two times with DCM. The organic layers were pooled, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative. TLC (DCM/MeOH 9:1; Rf range from 0.31 to 0.46 was scratched from the plate). The silicagel was taken up in 20 ml DCM/MeOH 1:1. The silicagel was filtered off. The filtrate was evaporated in vacuo to obtain the title compound as white solid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH:14](OC)[N:13]1[CH3:19])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]([Si](C)(C)C)[CH:21]=[CH2:22]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][C@H:14]([CH2:22][CH:21]=[CH2:20])[N:13]1[CH3:19])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC[Si](C)(C)C
Reactant: COC1CC[C@@H](C(=O)NCCc2ccccc2)N1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C
Reaction time: 0.33 h

Procedure:
A dichloromethane (20 mL) solution of 11C methylaminal (7.7 g, 20 mmol) is chilled to −78° C. After 20 minutes, allyltrimethylsilane (6.5 mL, 40 mmol) is added. After 10 more minutes 1 M titanium(IV) chloride (24 mL, 24 mmol) is added slowly by syringe. The reaction is complete after 1 hour. The resulting material is carefully quenched (frothing) with saturated bicarb and extracted with dichlormethane, then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The product is isolated by flash chromatography (SiO2), and it crystallizes upon standing. LCMS characterization ES+393.1 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:17])=[O:16])[CH:3]=1.[ClH:18]>C(O)C.[Pd]>[ClH:18].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:16])=[O:17])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 4 h
Yield: 100 %

Procedure:
Intermediate 75, 4-fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile (1.37 g, 5.4 mmol) was dissolved in ethanol (120 mL). To this was added 1N HCl (20 mL) and a catalytic amount of 10% Pd—C. The mixture was shaken under hydrogen at 55 psi for 4 h then filtered through Celite and concentrated to give the title compound as white solid (1.58 g, 100% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38 (1H, dd, J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2,7 Hz), 7.26 (2H, dd, J=21.4, 13.7 Hz), 3.93–3.84 (1H, m), 3.50–3.41 (3H, m), 2.40–2.31 (2H, m), 2.04–1.96 (2H, m). LCMS [M+H]+ calcd for C11H16N2O6FS: 259.087; found: 259.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[H-].[Na+].I[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:22])[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CI
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1C
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of Example 1 Step B (98.0 mg, 0.37 mmol) in DMF was added NaH (15.0 mg, 60% suspension in mineral oil, 0.37 mmol). After 10 min, iodomethane (0.023 mL, 0.37 mmol) was added, and the mixture was stirred for 2 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10%, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS C, tr=2.78 min, m/z 278.3 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.65 (app t, J=1.0 Hz, 1H), 7.31 (d, J=1.0 Hz, 2H), 7.20 (s, 1H), 4.05 (s, 3H), 2.95 (t, J=7.0 Hz, 2H), 1.79-1.72 (m, 2H), 1.43-1.26 (m, 6H), 0.90 (t, J=7.5 Hz, 3H).