Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbamate (92 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (51 mg, 74%). 1HNMR (DMSO-d6) 400 MHz δ: 8.55 (s, 1H), 8.09-8.04 (m, 1H), 7.98-7.93 (m, 1H), 7.70 (br s, 1H), 7.48 (d, J=6.9 Hz, 2H), 7.39-7.06 (m, 10H), 6.94-6.87 (m, 1H), 6.78-6.65 (m, 1H), 1.44-1.08 (m, 13H). LCMS: 542 [M+H].
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:17])[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:10]1[CH2:15][CH2:14][C:13](=[N:32][OH:33])[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(=NO)CC1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-1H-indole-2-carboxylic acid [1(S)-benzyl-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-amide (406 mg, 0.96 mmol) , hydroxylamine hydrochloride (80 mg, 1.15 mmol), and potassium carbonate, (159 mg, 1.15 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 18 h and concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (411 mg, 98%): HPLC (60/40) 5.13 minutes (97%); TSPMS 439/441 (MH+, 100%);
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:6]=1[C:7]([NH:9][CH:10]([C:12]1[N:13]=[N:14][N:15]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:16]=1[CH2:17][CH:18]=C(C)C)[CH3:11])=[O:8].[BH4-].[Na+]>CO>[Cl:4][C:5]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:6]=1[C:7]([NH:9][CH:10]([C:12]1[N:13]=[N:14][N:15]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:16]=1[CH2:17][CH2:18][OH:1])[CH3:11])=[O:8]
Reactant: CC(C)=CCc1c(C(C)NC(=O)c2cccc(C(F)(F)F)c2Cl)nnn1-c1ncccn1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NC(=O)c1cccc(C(F)(F)F)c1Cl)c1nnn(-c2ncccn2)c1CCO
Temperature: 25 °C
Yield: 70 %

Procedure:
A stream of O3 generated from an ozonator was passed though the solution of Intermediate 238 (200 mg, 0.43 mmol, 1.0 equiv.) in MeOH (30 mL) at −78° C. until the color of the reaction solution became blue (˜10 min). NaBH4 (49 mg, 1.3 mmol, 3.0 equiv.) was added at −78° C. The reaction solution was warmed to room temperature and partitioned between EtOAc and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography with EtOAc/hexanes as eluents to afford the title compound (140 mg, 0.30 mmol, 70% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.95-8.88 (d, J=4.9 Hz, 2H), 7.81-7.73 (dd, J=7.8, 1.7 Hz, 1H), 7.67-7.58 (dd, J=7.7, 1.6 Hz, 1H), 7.50-7.44 (t, J=4.9 Hz, 1H), 7.43-7.36 (t, J=7.8 Hz, 1H), 6.95-6.83 (d, J=8.1 Hz, 1H), 5.62-5.44 (m, 1H), 4.06-3.89 (m, 2H), 3.66-3.56 (ddd, J=14.7, 6.1, 4.6 Hz, 1H), 3.44-3.34 (ddd, J=14.7, 7.7, 4.9 Hz, 1H), 3.20-3.14 (t, J=5.9 Hz, 1H), 1.88-1.71 (d, J=7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 165.5, 159.0, 155.5, 147.4, 138.3, 133.1, 132.2, 129.2, 129.1 (q, JC—F=31.5 Hz), 128.5 (q, JC—F=5.2 Hz), 126.8, 122.5 (q, JC—F=273.4 Hz), 120.7, 61.1, 41.4, 27.3, 20.7. HRMS-ESI (m/z): [M+H]+ calcd for C18H17ClF3N6O2, 441.1048. found, 441.1038.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([NH:29][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NC(c1ccccc1)c1cccc(Cl)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccc(Cl)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3-chloro-phenyl)-C-phenyl-methylamine (CA [55095-14-2]).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:14]=2[CH:32]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:14]=2[CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1

Procedure:
6-[(5-Amino-1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=3)=[CH:9][C:8]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:7]=3[C:6]=2[CH2:5]1.[CH3:31]I.O>CN(C)C=O>[CH3:31][N:28]1[C:7]2[C:6]3[CH2:5][N:4]([CH3:3])[CH2:13][CH2:12][C:11]=3[C:10]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:22])[CH3:23])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[C:26](=[O:30])[C:27]1=[O:29]
Reactant: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)NC(=O)C3=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)N(C)C(=O)C3=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
NaH 60% (110 mg, 2.8 mmol) was added at 0° C. to a mixture of 8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1-H-pyrrolo[3,2-h]isoquinoline-2,3-dione (1 g, 2.5 mmol) in dimethylformamide (10 ml). The mixture was stirred at 0° C. for 10 min. Methyliodide (175 μl, 2.8 mmol) was added and the mixture was stirred or one hour at ambient temperature. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×25 ml). The organic phase was dried over sodium sulphate and evaporated. Pure 1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)- 6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione was obtained after purification on silica gel using dichloromethane/acetone/methanol (8:1:1) as the eluent. Yield 160 mg, m.p. 232-240° C. (decomposes).
Reaction SMILES: C([N:3](CC)CC)C.CS(Cl)(=O)=O.[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]([C@@H:25](O)[CH3:26])[CH2:21][O:22][CH2:23][CH3:24])([CH3:16])([CH3:15])[CH3:14].P(=O)(O)(O)O>C1COCC1>[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]([C@H:25]([NH2:3])[CH3:26])[CH2:21][O:22][CH2:23][CH3:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN(CC)CC
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)[C@H](C)O
Agent: CS(=O)(=O)Cl
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)[C@@H](C)N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.25 mL) and methanesulfonyl chloride (0.457 mL) were added to a solution of tert-butyl((2S,3S)-1-ethoxy-3-hydroxybutan-2-yl)carbamate obtained in the above-described Step 2 (1.06 g) in THF (20 mL), and the reaction solution was stirred at room temperature for 20 minutes. 10% Aqueous phosphoric acid solution was added to the reaction solution. Thereafter, the reaction solution was extracted with ethyl acetate and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. DMF (10 mL) and tetrabutylammonium azide (2 g) were added to the resultant residue, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was returned to room temperature, then diluted with diethyl ether, and washed with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate), and the solvent was evaporated under vacuum. THF (5 mL) and ethanol (5 mL) were added to the resultant residue, and 10% palladium on carbon (600 mg) was added under nitrogen atmosphere. The reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and the solvent was evaporated under vacuum to obtain tert-butyl((2R,3R)-3-amino-1-ethoxybutan-2-yl)carbamate as a colorless oily substance.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH:28]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl.O1CCCC1.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:34][CH3:33])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CC=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5 mL) at room temperature was added 2 M methylamine in tetrahydrofuran (0.4 mL) followed by 1 drop of acetic acid. The reaction was stirred at room temperature for 2 h followed by an addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction was stirred overnight. It was then purified by flash chromatography to give 10 mg of the title compound (19.4%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[C:8]([Mg]Br)#[CH:9].P([O-])(O)(O)=O.[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:7])[C:8]#[CH:9]
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccco1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 g of 2-furaldehyde in 30 ml of tetrahydrofuran were cooled to 0° C. and 50 ml of a 0.5M solution of ethynyl magnesium bromide in tetrahydrofuran were added dropwise over 15minutes. The mixture was stirred for 1 hour at 0° C., poured into a saturated aqueous sodium dihydrogenphosphate solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 2.5 g of the expected product after chromatography on silica (eluent: 75/25 hexane/ethyl acetate).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].Cl[C:10]1[N:14]2[N:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:13]2=[N:12][N:11]=1>C1COCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:16]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:18][C:13]2[N:14]([C:10]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][N:12]=2)[N:15]=1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Reactant: OC1CCCCC1
Agent: [Na]
Solvent: C1CCOC1
Product: Clc1ccc(-c2cc3nnc(OC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.6 %

Procedure:
To a solution of cyclohexanol (0.5 g, 5 mmol) in anhydrous THF (1 mL) at room temperature was added freshly cut sodium metal (35 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 20 min, then at 60° C. for 30 min, and then allowed to cool to room temperature. Into this mixture was added 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (115 mg, 0.3 mmol), the resulting mixture was stirred at room temperature under argon for 16 h. The reaction was carefully quenched by addition of methanol, then diluted with EtOAc. The solution was washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated. The obtained residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 10 mg (7.6%) of the title compound as a pale-yellow solid. HPLC/MS (method A): retention time=4.06 min, (M+H)+=439.1. 1H NMR (CDCl3, 400 MHz): δ 7.84 (s, 1H), 7.46 (dd, J=5.62, 3.67 Hz, 1H), 7.32-7.37 (m, 2H), 7.25-7.30 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.03-7.08 (m, 2H), 5.21-5.29 (m, 1H), 2.28 (d, J=12.96 Hz, 2H), 1.88 (d, J=4.40 Hz, 2H), 1.60-1.80 (m, 3H), 1.45-1.52 (m, 2H), 1.20-1.40(m, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-1-methyl-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 89) (370 mg, 0.93 mmol) and N-methylmorpholine (170 μl, 1.54 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (130 μl, 1.00 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (380 μl, 3.10 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a colourless oil (330 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[N:18]([CH3:23])[C:17]3[CH2:24][CH:25]4[NH:29][CH:28]([C:16]=3[C:15]=2[C:14]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reactant: Cc1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: Cc1cccc(S(=O)(=O)c2cc(C)c3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 29 %

Procedure:
Intermediate 10 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, (8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-methyl-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (85 mg, 29%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.97-8.05 (m, 1H), 7.71-7.78 (m, 2H), 7.29-7.38 (m, 3H), 5.23 (br s, 1H), 4.72 (br s, 1H), 3.83 (s, 3H), 3.33 (br s, 1H), 2.74 (s, 3H), 2.45 (d, J=16.2 Hz, 1H), 2.38 (s, 3H), 2.11-2.35 (m, 2H), 1.88-1.97 (m, 1H), 1.55-1.64 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1ccc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)ccc1O
Temperature: 130 °C
Reaction time: 12 h

Procedure:
3-(3-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (2.30 g) was dissolved in N,N-dimethylformamide (25 mL), and lithium chloride (2.97 g) was added to the solution, and then the mixture was stirred at 130° C. for 12 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (g).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C@@H:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4]
Reactant: N[C@H](C(=O)O)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)C1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (S)-2-amino-2-cyclopentylacetic acid (1.00 g, 6.98 mmol) in THF (20 mL) was added dropwise a solution of LiAlH4 in THF (1.0 M, 10.5 mL, 10.5 mmol) at 0° C. under N2. The reaction was allowed to warm to ambient temperature and heated at reflux overnight. After cooling, the reaction mixture was cooled to 0° C. and carefully quenched by dropwise addition of water (0.4 mL) followed by 15% NaOH solution (0.4 mL) and water (1.2 mL). The mixture was stirred at ambient temperature for 15 minutes and filtered through Celite. The filtrate was concentrated to give crude (S)-2-amino-2-cyclopentylethanol, which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(OC(F)(F)F)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-trifluoromethoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O4, 416.1; m/z found, 417.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.06-12.92 (m, 2H), 8.99 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.22 (dd, J=8.4, 1.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (s, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.46-7.40 (m, 1H).
Reaction SMILES: [C:1]([P:5](=[O:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C(OCC)OCC)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([PH:5](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)P(=O)(Cc1ccccc1)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[PH](=O)Cc1ccccc1

Procedure:
Following a procedure analogous to that to Example 13, but using tert.butyl(benzyl)(diethoxymethyl) phosphine oxide (1.7 g) and 15 ml of concentrated hydrochloric acid, tert.butyl(benzyl) phosphine oxide is obtained as a white solid, m.p. 80°-2° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:28])[N:11]3[C:24]([O:26][CH3:27])=[O:25])[CH2:2]1.[CH3:29][C:30]([CH3:32])=O>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH:30]([CH3:32])[CH3:29])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24]([O:26][CH3:27])=[O:25])[C@@H:10]([CH3:28])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:22][CH2:23]1
Reactant: CC(C)=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(C)C)C3)c2CC[C@@H]1C

Procedure:
(S)-Methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (S)-methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and acetone according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.85-0.95 (m, 6H), 1.05-1.15 (m, 7H), 1.45-1.55 (m, 1H), 2.15-2.52 (m, 3H), 2.80-2.90 (m, 1H), 3.01-3.11 (m, 2H), 3.40-3.50 (m, 2H), 3.67-3.71 (m, 1H), 3.78 (s, 3H), 4.15-4.25 (m, 1H), 4.51-4.62 (m, 1H), 7.20-7.35 (m, 2H), 7.76 (s, 1H), 7.97 (s, 1H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([N:15]([CH3:14])[CH2:16][CH2:17][OH:18])=[O:13])=[O:4]
Reactant: CNCCO
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NC(=O)N(C)CCO
Yield: 72.5 %

Procedure:
A solution of 2-methoxycarbonyl phenylisocyanate (21.7 g) in ethyl acetate (116 g) is added dropwise to N-methylethanolamine (22.5 g), the mixture being stirred and cooled to keep the temperature below 36° C. The upper layer of the resulting mixture is separated and distilled at 60° C. under reduced pressure to remove ethyl acetate. The white solid residue remaining is triturated with ether, filtered, washed with ether and then dried in air to give N-(2-methoxycarbonylphenyl)-N'-methyl-N'-(2-hydroxyethyl)urea (22.4 g), m.pt. 90° C.