Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[NH:25][N:24]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:31][C:32](OC(C)=O)=[O:33]>C1COCC1.O>[C:32]([N:25]1[C:26]([CH:28]2[CH2:29][CH2:30]2)=[CH:27][C:23]([NH:22][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]3[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])(=[O:14])=[O:15])=[CH:10][CH:9]=3)[N:4]=2)=[N:24]1)(=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCNS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2Br)cc1C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (200 mg, 0.39 mmol) in THF/H2O (2 mL/2 mL), Ac2O (0.2 mL, 1.95 mmol, 5.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was filtered, and the solid was concentrated with ethanol to bring residual water off to afford crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (used for the next step without further purification). LC-MS (m/z)=556.0, 558.0 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([CH3:12])[C:7]=1[O:8][CH:9]([F:11])[F:10].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[ClH:1].[F:10][CH:9]([F:11])[O:8][C:7]1[N:6]([CH3:12])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:2][S:19][C:18](=[NH:17])[NH2:20]
Reactant: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F
Reactant: NC(N)=S
Solvent: CCO
Product: Cl
Product: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 3.7 g (purity: 83.4%, 11.7 mmol) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole in 20 ml of ethanol was added 0.8 g (11.1 mmol) of thiourea, followed by stirring at room temperature overnight and further heating and stirring at 50° C. for 1 hour. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 3.8 g (yield: 96.4%) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrochloride as white crystals (melting point: 117 to 119° C.)
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[OH:4].[F:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[F:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]([NH:1][CH:2]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH:3]([OH:4])[C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:9]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.8 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (311 mg, 0.73 mmol) in N,N-dimethylformamide (10 ml) were added 4-fluoronaphthalene-1-carboxylic acid (133 mg, 0.70 mmol) and 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) was finally added. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 1:2) and recrystallization (hexane-ethyl acetate) to give 4-fluoro-N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide (217 mg, 52%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: CN(C)CCCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 25.61 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (7.38 g, 51.23 mmol) were weighed into a round bottom flask and stirred in DMF (50 mL). To this solution/suspension was added potassium carbonate (21.59 g, 156.2 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then poured into ice water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (1×) and brine (1×). The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was chromatographed in 0-20% (2M NH3 in MeOH) in 1:1 dichloromethane and ethyl acetate, giving a yellow solid. Yield: 5.8 g, 84%. 1H NMR (CDCl3) δ 8.14 (dd, 1H, J=9.0, 3.0 Hz) 8.06 (d, 1H, J=3.0 Hz), 7.16 (d, 1H, J=9.0 Hz), 4.08 (t, 1H, J=7.5 Hz), 3.00 (t, 1H, J=7.5 Hz), 2.70 (t, 1H, J=7.5 Hz); 2.51 (t, 1H, J=7.5 Hz), 2.31 (s, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12>CN(C)C=O>[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH:41][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
Diisopropylethylamine (DIEA, 0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.05 g, 0.23 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.096 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (0.048 g, 0.023 mmol) was added and allowed to react for approximately 30 minutes, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.92 (s, 1H), 8.54 (d, J=7.0 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.73 (m, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.44 (m, 3H), 7.26 (dd, J=5.5, 6.8 Hz, 1H), 6.90 (dd, J=5.5, 6.8 Hz, 1H), 3.96 (s, 3H); LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[CH2:37]([CH:39]([NH2:42])[CH2:40][CH3:41])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:42][CH:39]([CH2:40][CH3:41])[CH2:37][CH3:38])=[O:25]
Reactant: CCC(N)CC
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCC(CC)NC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 1-ethylpropylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1

Procedure:
(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (29a, 100 mg, 0.24 mmol) was dissolved in MeCN (3 mL), triethylamine (0.104 mL, 0.75 mmol) was added followed by addition of cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol). The reaction was followed by LC/MS. After 1 hour approximately 50% conversion was detected, more reagents cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added in an attempt to increase conversion without any success. The reaction was quenched by addition of saturated NH4Cl (aq) and concentrated. The residual material was purified by HPLC, collected fractions was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm, one major peak at 32.39 min (99.7%) and one minor peak at 30.69 min (0.3%).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:20][CH:21]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To an ice-bath cooled mixture of phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 3, 3.0 g) and 1 mL of CH2Cl2 was added drop-wise 3.0 mL of chlorosulfonic acid (5.2 g, 5.0 eq). After the addition of the chlorosulfonic acid was complete the ice bath was removed. The mixture was continued to stir at room temperature for 3 h. Thereafter the thick syrupy mixture was poured onto the crushed ice with vigorous stirring. White precipitates were collected by filtration, were washed with methanol and cold benzene, and dried overnight under high vacuum to yield 3.4 g (87%) of Intermediate 4 as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:30])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:28][CH2:29]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Reactant: N
Product: NC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 44.9 %

Procedure:
A 10-mL vial was charged with ethyl 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate (0.070 g, 0.17 mmol) and NH3 (4.9 mL, 7N in methanol, 34.2 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. The crude reaction solution concentrated under reduced pressure. The residue was absorbed on silica (2 g) then purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.029 g, 45%) as a white solid. M.p. 232-235° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.5, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75-7.69 (m, 1H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 7.50 (br s, 1H), 6.93 (br s, 1H), 3.37 (s, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09 (m, 2H); 1.06-1.00 (m, 2H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][N:32]5C(OC(C)(C)C)=O)=[O:30])[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:43])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>CO.CCOCC>[ClH:44].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][NH:32]5)=[O:30])[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:43])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1)C2
Yield: 85 %

Procedure:
(S)-tert-Butyl 2-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)pyrrolidine-1-carboxylate (55 mg, 0.094 mmol) was stirred in a mixture of MeOH (2 mL) and 2 N HCl in Et2O (8 mL) for 5 h. The reaction mixture was concentrated to provide the title compound (42 mg, 85%) as a yellow-green solid: mp 220-226° C.; 1H NMR (500 MHz, CD3OD) δ 7.79 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H), 7.39-7.36 (m, 1H), 7.04 (dd, J=8.3, 1.6 Hz, 1H), 6.57-6.55 (m, 1H), 6.34 (d, J=2.5 Hz, 1H), 5.27 (s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H), 3.48-3.34 (m, 3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, 1H), 2.17-2.02 (m, 3H); ESI MS m/z 483 [M+H]+; HPLC (Method B) 95.5% (AUC), tR=13.5 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[N:5][N:4]=[N:3]1.[OH:13]O>C(O)=O.O>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:13]
Reactant: Cn1nnnc1SCCCCBr
Reactant: OO
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)CCCCBr
Temperature: 25 °C

Procedure:
1-Methyl-5-(4-bromobutyl)thio-1,2,3,4-tetrazole prepared in Reference Example 2 is dissolved in formic acid (50 ml). 30% Aqueous hydrogen peroxide (2.3 g) is added to the solution with stirring at room temperature and the mixture is allowed to stand at room temperature for 2 overnights. The mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off to obtain 1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutyl sulfoxide (5.5 g) as colorless liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][N:13]=1.[C:21]1(/C(/C)=C/CNC(=O)C2C=CC=CC=2)C=CC=CC=1>>[CH3:21][C:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[N:13][CH2:12][CH:11]1[OH:14]
Reactant: C/C(=C\CNC(=O)c1ccccc1)c1ccccc1
Reactant: OC1CN=C(c2ccccc2F)OC1c1ccccc1
Product: CC1(c2ccccc2)OC(c2ccccc2)=NCC1O

Procedure:
(5RS, 6SR)-6-Methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol may be obtained in the following manner: working as in Example 22 for the preparation of (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol, but starting with (E)-N-(3-phenyl-2-buten-1-yl)benzamide (4.2 g), a 0.35 M solution (48 cc) of 3-chloroperbenzoic acid in dichloromethane and boron trifluoride etherate (2.6 g), and after purification of the oil obtained by chromatography on a column (height: 35 cm; diameter: 3 cm) of silica (0.2-0.063 mm), eluting with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting 30-cc fractions, fractions 9 to 17 being combined and concentrated to dryness under reduced pressure (4 kPa) at 45° C., followed by recrystallization of the residue obtained in isopropyl ether, (5RS, 6SR)-6-methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.65 g, m.p. 130° C.) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:40][CH:39]=2)[CH:8]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 65.3 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (312 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (1.0 g) according to an analogous synthetic method to Example 110, the title compound (360 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:28][O:27]1.[NH:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:29]1([CH2:28][CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[OH:27])[CH2:35][CH2:34][CH2:33][N:32]([CH2:14][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:31][CH2:30]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: C1CNCCNC1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Product: Cc1c(C(O)CN2CCCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
The reaction was run in a similar fashion to general epoxide opening conditions as shown for EXAMPLE 2 (at 150° C. for 60 min) starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and 1,4-diazepane. Purification by preparative TLC (MeOH/DCM=1:15) afforded 5,5′-[1,4-diazepane-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one) The resulting mixture of isomers was then separated to all three pure diastereomers by SFC chiral chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][C@@H:5]([CH:7]=O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[ClH:15].[N+:16]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]([N:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[ClH:15].[ClH:15].[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]([N:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:7][CH:5]3[CH:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:3][C:2](=[O:1])[CH2:6]3)[CH2:33][CH2:32]2)[CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:37][CH:38]=1)([O-:18])=[O:17]
Reactant: O=C[C@@H]1CC(=O)C[C@H]1c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(=O)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
To a solution of (+−)-trans4-oxo-2-phenylcyclopentanecarboxaldehyde from Step D (327 mg, 1.74 mmol) in 1,2-dichloroethane (20 mL) was added 4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride (667 mg, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol). After 5 min, sodium triacetoxyborohydride (740 mg, 3.5 mmol) was added and the reaction was stirred at rt for 4 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC eluting with a gradient of 35 to 75% ethyl acetate in hexanes to give the title product (365 mg) as the free amine. This was taken up in ether and 1M hydrogen chloride in ether (0.5 mL) was added to form the di-hydrochloride salt. The volatiles were removed in vacuo to give the title salt.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:32])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:18][C:17]=2[CH:31]=1.CI>O1CCCC1>[F:28][C:22]([F:27])([C:23]([F:24])([F:25])[F:26])[C:21]([F:30])([F:29])[C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:12]([CH3:1])[C:11]([O:10][CH3:9])=[O:32])=[CH:31][C:17]=2[N:18]=1
Reactant: COC(=O)Cc1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethyl benzene/heptane, 15.32 ml, 0.0306 mol) was added dropwise to a solution of methyl(2-heptafluoropropylbenzoxazol-5-yl)acetate (11.0 g, 0.0306 mol) in tetrahydrofuran (175 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (39.1 g, 0.275 mol) in tetrahydrofuran (25 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 3 hours. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g) as a reddish oil, which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:22][CH2:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:19][CH2:18]3)[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:33])[CH:8]=1.Br>O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:33])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(c3cccc4c(NCc5ccc(Cl)c(Cl)c5)cc(C)nc34)CC2)cc1
Agent: Br
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(N3CCNCC3)c2n1
Product: Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 149.4 %

Procedure:
(3,4-Dichlorobenzyl)-{2-methyl-8-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-quinolin-4-yl}-amine (example 17, 40 mg, 0.072 mmole) and a mixture of HBr/glacial acetic acid (33%, 1 mL)/0.2 mL) were stirred at 70° C. for 3 hrs. The content of the flask was diluted with water and extracted with ethyl acetate. The aqueous phase was alkalized and extracted with dichloromethane. The organic phases were washed with saturated NaCl solution and concentrated. The residue was crystallized as hydrochloride from isopropanol/iso-propyl ether/ethanol/HCl to give a light fawn salt (17 mg, 50%).