Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2].[CH3:41]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][N:33]([CH3:41])[CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCNC3)cc1)C2c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCN(C)C3)cc1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of Example 45 (TFA salt, 7 mg, 0.01 mmol) in DCM (0.5 ml) were successively added AcOH (0.001 ml, 0.021 mmol), formaldehyde (37% in water, 0.002 ml, 0.021 mmol) and NaBH(OAc)3 (4.4 mg, 0.021 mmol) at RT. The reaction mixture was stirred at RT for 1 h, then diluted into DCM and washed with a 2M aqueous Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt, 7.4 mg, 0.01 mmol, quant.) as a colorless solid. HPLC: AtRet=2.11 min; LC-MS: m/z 576.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 0.83-0.92 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.10-1.20 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.44-1.67 (m, 4H), 1.69-1.87 (m, 2H), 2.04-2.19 (m, 1H), 2.65-2.81 (m, 5H), 2.84-2.93 (m, 3H), 3.08-3.19 (m, 1H), 3.22-3.41 (m, 3H), 3.56 (d, J=20.0, 1H), 3.72 (s, 3H), 3.91 (d, J=20.0, 1H), 4.17-4.27 (m, 1H), 5.91-5.96 (m, 1H), 6.58-6.63 (m, 2H), 6.83 (s, 1H), 6.88-6.94 (m, 2H), 6.98-7.02 (m, 1H), 7.32-7.37 (m, 4H).
Reaction SMILES: [I:1][C:2]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:6](=O)[NH:7][C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1.CSC>C1COCC1>[I:1][C:2]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[CH2:6][NH:7][C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(I)nn2c1C(=O)NC1(CC1)C2
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)c1c(I)nn2c1CNC1(CC1)C2
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of Intermediate 350B (1.1 g, 3.05 mmol) in THF (10 mL) was added BH3.DMS (0.578 mL, 6.09 mmol, 2M) and the resulting solution was stirred at 40° C. for 18 h. The reaction mixture was cooled to RT, quenched with ethanol (10 mL) and heated to reflux for 1 h. Reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 350C (0.7 g, 66%) as a gummy solid. MS(ES): m/z=348 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[NH2:23][C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][C@@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:23][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: COC(=O)C[C@H](N)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 77.9 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 130 mg of methyl(S)-3-amino-3-(2-chlorophenyl)propionate were dissolved in 5 ml of dichloromethane and 0.52 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane and washed repeatedly with 20 ml of 25% aqueous ammonia solution, until the organic phase was colorless. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (191 mg) with a molecular weight of 402.9 g/mol (C17H23ClN2O5S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([O:23][CH3:24])[CH:14]=1)(=[O:11])[CH3:10].CN1CCOCC1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:35]=[CH:36][C:37]([N:40]([C:17](=[O:19])[C:16]2[CH:20]=[C:21]([Cl:22])[C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:14][C:15]=2[O:23][CH3:24])[NH2:41])=[CH:38][CH:39]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N(N)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Iso-butylchloroformate (1.6 ml, 16.4 mmol) was added dropwise to a solution of 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (4 g, 16.4 mmol) and 4-methylmorpholine (1.8 ml, 16.4mmol) in 400 ml of anhydrous THF at 0° C. and stirred for 0.5 h at room temperature before addition of 4-(trifluoromethyl)phenylhydrazine (2.9 g, 16.4 mmol) dissolved in 80 ml of the same solvent. The reaction mixture was stirred 8 h, diluted with ethyl acetate (1 vol), washed with water, saturated NaHCO3 solution, and brine. Concentration gave a solid which was recrystallized from acetonitrile 5.7 g (86%); mp 217°-219° C.; IR(KBr, ν=cm-1) 3410, 3286, 1704, 1670, 1500, 1338, 1238, 1104; 1H NMR (300 MHz, DMSO-d6) δ2.15 (3H, s), 3.88 (3H, s), 6.88 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 7.68 (1H, s), 7.76 (1H, s), 8.61 (1H, br. s), 9.62 (1H, br. s) 10.01 (1H, br. s); MS(ESI)m/z: 400 (M--H-)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:12]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([OH:13])[C:11]([F:19])([F:18])[Cl:10]
Reactant: CCOc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(O)(C(F)(F)F)C(F)(F)Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of ethoxybenzene (67 g), chloropentafluoroacetone (100 g) and aluminium chloride (7 g) was charged to a Hastalloy lined cell at -78° C., the cell sealed and heated to 120° C. for 8 hours. After cooling and venting, the residue was taken up in chloroform and filtered through silica gel. After removal of the solvent by evaporation the residual solid was recrystallised from n-hexane to yield several crops of 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)-3-chloropropan-2-ol. (Total 70 g) mp. 84°-86° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[CH2:24]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[CH3:25]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CCI
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 65 °C
Reaction time: 72 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (120 mg, 0.359 mmol) from Step A of Example 256, iodoethane (0.287 mL, 3.59 mmol), and triethylamine (0.750 mL, 5.38 mmol) were in tetrahydrofuran (1 mL). The reaction was stirred at 65° C. for 3 days, and then the solvent was removed in vacuo. The residue was diluted with dichloromethane (5 mL), and addition of saturated aqueous sodium bicarbonate gave the products as a solid. This material was purified using a 12 g silica gel cartridge with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give two products. The second product was further purified on 4×0.25 mm preparative thin-layer chromatography plate eluting with 6% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17-8.19 (m, 2H), 7.93-7.95 (m, 2H), 3.38 (dd, J=9.8, 3.1 Hz, 1H), 3.15 (dd, J=9.6, 3.2 Hz, 1H), 3.06 (dd, J=9.8, 8.0 Hz, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.78 (q, J=6.1 Hz, 1H), 2.44-2.58 (m, 4H), 2.25-2.33 (m, 1H), 1.85-1.92 (m, 1H), 1.75-1.85 (m, 1H), 1.16-1.34 (m, 2H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([NH:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][CH:2]([CH3:21])[CH:3]([NH:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Nc1nnc(-c2ccccc2)o1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)O
Reaction time: 1 h
Yield: 50 %

Procedure:
Crude ethyl 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoate (assumed 5 mmol) was dissolved in a mixture of THF (10 ml) and MeOH (2 ml) and then treated dropwise (exothermic) with aqueous 1 N NaOH (6 mL) solution. The reaction was stirred for 1 h, diluted with H2O (50 mL) and then extracted with Et2O (1×50 mL). The aqueous layer was acidified to pH 3 with aqueous 1N HCl solution and then extracted with EtOAc (3×35 mL). The EtOAc extracts were combined, washed with sat. aqueous NaCl solution, dried (MgSO4) and the solvent was removed in vacuo to give 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoic acid in 50-75% yield over 3 steps in purity >90% as judged by LCMS. MS found: 262 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:33])/[C:15](/[Sn](CCCC)(CCCC)CCCC)=[CH:16]\[CH:17]([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=1.O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:34][C:35]1[CH:40]=[CH:39][C:38](/[C:15](=[CH:16]/[CH:17]([CH3:18])[CH3:19])/[C:14]([NH:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:33])=[CH:37][CH:36]=1
Reactant: Clc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/C(C)C)C(=O)NCCc1ccc(OC)c(OC)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)/C(=C\C(C)C)c2ccc(Cl)cc2)cc1OC
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
A solution of 10 g (17.6 mmol) of (2E)-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methyl-2-(tributylstannyl)-2-pentenamide (5) in 15 ml of dimethylformamide (DMF) was mixed with 4.2 g (17.7 mmol) of 4-chloroiodobenzene, 0.5 g of Pd(PPh3)4 and 0.5 g of copper(I) iodide. After stirring for approximately 14 hours at 20 to 25° C., the reaction solution was poured into water and extracted with MTBE. The organic phases were washed with water, dried and freed from the solvent. After chromatographing on silica gel (cyclohexane:MTBE [7:1 to 1:1]), 5.8 g of the title compound were obtained.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]#[N:22])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:21](=[NH:22])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)=[N:12]3)=[CH:26][CH:25]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 0 °C
Yield: 55.1 %

Procedure:
To a cooled (ice bath) and stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile (example 80, step A) (285 mg, 1.0 mmol) in THF (5 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (6 ml, 6.0 mmol), the reaction mixture was heated under reflux conditions for 92 h and poured into ice-water (20 ml). 2N HCl (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N NaOH (5 ml) was added and the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light red foam (210 mg, 55%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.[CH:16]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:16]1([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][NH2:5])[CH2:25][CH2:26]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C1CCC(N2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCCCN1CCN(C2CCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-(3-bromopropyl)phthalimide (0.8 g, 3.0 mmol), 1-cyclopentylpiperazine (0.46 g, 3.0 mmol), and K2CO3 (1.66 g, 12.0 mmol) in CH3CN (30 mL) was heated to reflux for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The filtrate was concentrated, treated with 6N HCl (9.0 mL) and acetic acid (18.0 mL), heated to reflux overnight, and concentrated. The residue was treated with potassium carbonate (1.66 g) in CH3CN (30 mL) for 1 hour. After filtration of the solid, the solvent was evaporated to provide the desired product. MS (DCI/NH3) m/e 212 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.04 (br s, 2H), 3.68 (m, 4H), 3.41 (m, 4H), 3.21 (m, 2H), 2.91 (m, 2H), 2.0 (m, 4H), 1.84-1.73 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[OH:34])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH3:15].O>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:14]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[O:34][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH3:15]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: C=CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC

Procedure:
Add undec-10-enoyl chloride (2 g.) in benzene (6 cc.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°. Keep the mixture at -10° for 17 hours, add to water and extract with benzene. Wash, dryand evaporate the extracts and recrystallize the residue from ethanol to obtain the title compound, m.p. 87°-88°; ultraviolet absorption peak at 240 mμ (ε17,000); infrared absorption peaks at 5.79, 6.00, 6.20 μ.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16].[NH4+].[Cl-]>C1COCC1>[C:15]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:17])[CH3:16]
Reactant: Nc1cccnc1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
To a solution of 2-chloro-3-pyridinamine (14.9 g, 116 mmol) in 300 mL of THF was added K2CO3 (32 g, 232 mmol) and acetyl chloride (12 mL, 169 mmol) and the mixture was stirred at room temperature overnight. Saturated NH4Cl was added and the product was extracted in EtOAc, dried over Na2SO4, and filtered through silica to yield 20.81 g of the title amide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:9]([CH2:10][N+:11]([O-:13])=[O:12])[C:8]1[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CN(C)C(=S)[S-]
Reactant: CC(=O)Oc1ccc(C=C[N+](=O)[O-])cc1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(=O)Oc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of 4-acetoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 4-acetoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 116° C.-118° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([NH:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11].Cl.O1CCOCC1>>[CH3:17][C:9]([NH:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[CH3:41])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)([CH3:8])[C:10]([OH:12])=[O:11]
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NC(C)(C)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (R)-tert-butyl 2-methyl-2-(3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanamido)propanoate 2,2,2-trifluoroacetate (2.0 mg, 3.37 mol) was added 4M hydrogen chloride in dioxane (0.295 mL, 1.181 mmol). The reaction was stirred at room temperature for 4 h. The mixture was concentrated to give the title compound. LCMS m/z=423.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].C(Cl)(=O)C([Cl:21])=O.C(=O)=O>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:21])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCCCCCC(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCC(F)(F)F

Procedure:
Dissolve 12,12,12-trifluorododecanoic acid (244 mg, 0.96 mmol) in methylene chloride (5 mL) and add dimethylformamide (3 drops). Add oxalyl chloride (85 μL, 0.96 mmol) and stir until evolution of carbon dioxide is complete to give 12,12,12-trifluorododecanoyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH2:22]O)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])(C(C)(C)C)(C)C.[CH3:41][C@@H:42]1[NH:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]1>>[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[C:24]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:38])[N:12]([CH2:11][C:10]([CH3:39])([CH3:40])[CH2:9][OH:8])[CH:21]=[C:20]4[CH2:22][N:47]3[CH2:46][CH2:45][NH:44][CH2:43][C@@H:42]3[CH3:41])[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=2)[CH2:32][CH2:31]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@@H]3C)c2c1
Yield: 14.1 %

Procedure:
The title compound was synthesised by a similar method to Example 26 h using 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (0.54 g), and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.191 g). Purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.072 g) as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[S:7])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH:20][CH:21]1[CH2:24][O:23][CH2:22]1.N1C=CC=CC=1>O>[O:23]1[CH2:24][CH:21]([O:20][C:6](=[S:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH2:22]1
Reactant: OC1COC1
Reactant: CC(C)c1ccccc1C(=S)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1ccccc1C(=S)OC1COC1
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 12.9 g of 2-isopropylthiobenzoic acid chloride and 20 ml of absolute toluene is added dropwise at a temperature of from 15° to 20° C. to a mixture of 4.44 g of 3-hydroxy-oxetane, 6.64 g of pyridine and 60 ml of absolute toluene. The resulting suspension is stirred for 2 hours at a temperature of from 20° to 25° C. and for a further 3 hours at a temperature of from 40° to 45° C. Water is added to the reaction mixture and the organic phase is washed with water, dried and concentrated by evaporation to yield 12.6 g of 2-isopropylthiobenzoic acid oxetan-3-yl ester in the form of a pale yellow oil.
Reaction SMILES: NC1C=C(OC)C=C(OC)C=1C(N)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[NH:25][C:24](=O)[O:23][C:21](=[O:22])[C:20]2=[C:27]([O:29][CH3:30])[CH:28]=1.COC1C=C(N)C(=C(OC)C=1)C(O)=O.C(Cl)(Cl)=O.COC1C=C(C=C(OC)C=1)N.C(Cl)(=O)C(Cl)=O>>[CH3:30][O:29][C:27]1[CH:28]=[C:17]([O:16][CH3:15])[CH:18]=[C:19]2[C:20]=1[C:21](=[O:22])[C:24](=[O:23])[NH:25]2
Reactant: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1
Agent: COc1cc(N)c(C(=O)O)c(OC)c1
Agent: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(N)cc(OC)c1
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2

Procedure:
2-Amino-4,6-dimethoxybenzamide has been prepared from 4,6-dimethoxyisatoic anhydride. The 4,6-dimethoxyisatoic anhydride was, in turn, prepared by a reaction of 4,6-dimethoxyanthranilic acid with phosgene (U.S. Pat. No. 4,191,840 and Org. Synth. 1947, 27, 45). A different route converts 3,5-dimethoxyaniline to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin. The isatin is converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCI/HOBt-mediated coupling to produce 2-amino-4,6-dimethoxybenzamide (WO 2008/92231).