Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].N1C=CC=CC=1>ClC(Cl)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: Nc1ncccc1C(=O)c1cccs1
Reactant: O=C(Cl)CCCCCBr
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CCCCCBr)Nc1ncccc1C(=O)c1cccs1

Procedure:
2-Amino-3-(2-thenoyl)pyridine is reacted with 6-bromohexanoyl chloride in the presence of pyridine in dichloroethane to give 2-(6-bromohexanoylamino)-3-(2-thenoyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC1CCCc2c(Br)cncc21
Temperature: 0 °C
Yield: 92 %

Procedure:
A suspension of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate A-1[C]) (2.135 g, 9.44 mmol) in MeOH (18.9 mL) was cooled to 0° C. and treated with NaBH4 (357 mg, 9.44 mmol) in 5 portions over 30 min. The reaction was stirred for ¾ h at 0° C., then AcOH was added dropwise until pH ˜5-6 and the reaction mixture was evaporated. The residue was diluted with water and poured on aq. sat. NaHCO3-solution followed by extraction with EtOAc (3×). The organic layers are washed once with aq. sat. NaHCO3 and aq. 10% NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was precipitated with CH2Cl2/n-pentane to afford the title compound (1.98 g, 92%) as dark brown viscous oil. MS: 227 (M+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=C(C#N)[CH:17]=[C:16]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1.[OH-:23].[Na+].[CH2:25]([OH:27])[CH3:26]>>[Cl:1][C:2]1[CH:19]=[C:26]([CH:17]=[C:16]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)[C:25]([OH:23])=[O:27]
Reactant: Cc1cc(CCCCCOc2c(Cl)cc(C#N)cc2Cl)on1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: Cc1cc(CCCCCOc2c(Cl)cc(C(=O)O)cc2Cl)on1

Procedure:
A mixture of 6.11 g 5-[5-(2,6-dichloro-4-cyanophenoxy)pentyl]-3-methylisoxazole (m.p. 59°-60° C.), 75 ml 35% sodium hydroxide and 75 ml ethanol was stirred on a steam bath for several hours. The reaction mixture upon standing separated into a clear lower layer and a yellow upper layer. The latter was separated, diluted with cold water and acidified with hydrochloric acid. The resulting solid was collected and recrystallized from acetonitrile to give 5.24 g 3,5-dichloro-4-[5-(3-methylisoxazol-5-yl)pentyloxy]benzoic acid, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][CH2:15][CH2:14][CH:22]([CH3:21])[CH3:17].[CH3:1][S:2]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:22]3[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]=3[S:16][C:15]=2[CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3)c(Cc3cccc4ccccc34)sc21
Product: CCCC(C)C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.028 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, saturated sodium hydrogen carbonate solution (10 ml) was added and the mixture was extracted with ether (2×10 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative normal-phase HPLC with isohexane:ethyl acetate gradient elution then recrystallised from ethyl acetate:isohexane to give the title compound (28 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][CH3:11].[H-].[Na+].[C:14]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br)([O:16][CH3:17])=[O:15].CCCCCC.C(OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:16][C:14](=[O:15])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCc1c(O)cccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(O)cccc1OCc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
A mixture of 1,3-dihydroxy-2-propylbenzene (5.00 g, 33.3 mmol) in dimethylformamide (10 mL) was treated with 97% sodium hydride (880 mg, 36.6 mmol ) as room temperature for 20 minutes. 2-(Carbomethoxy)benzyl bromide (7.62 g, 33.3 mmol) was added in one portion and the resulting mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate and washed once with brine. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide a brown oil. Silica gel chromatography (hexane/ethyl acetate) provided 2.10 g (21%) of the title intermediate as a colorless oil: 1H--NMR (CDCl3), 8.08 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.61 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.02 (t, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 5.52 (s, 2H), 5.16 (s, 1H, --OH), 3.94 (s, 3H), 2.78 (t, J=7 Hz, 2H), 1.67 (hextet, J=8 Hz, 2H), 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cc2Cl)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 4-(5-carboxy-3-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (1.1 g, 3.22 mmol) and K2CO3 (0.67 g, 4.83 mmol) in DMF (10 mL) was added dropwise MeI (0.3 mL, 4.83 mmol) with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 h, quenched with 20 mL of satd. aq. solution of NaHCO3 and extracted with EtOAc (50 mL). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient 30% to 50% EtOAc in hexane) to give the title compound as white solid.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:27][CH:26]=1)(=[O:19])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(OCC(O)CCc2cccnc2)cc1
Yield: 21.4 %

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.05 g), 4-hydroxybenzophenone (1.35 g), ethanol (30 ml) and aqueous sodium hydroxide (1.4 M, 5 ml). After work up the residue was purified by column chromatography over silica with ether then ethyl acetate to give the title compound as an oil (0.42 g).
Reaction SMILES: O1CCC[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[O:20][C:19]([CH3:27])([CH3:26])[CH2:18][C:17]2=O>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:2])[O:20][C:19]([CH3:27])([CH3:26])[CH:18]=[CH:17]2
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOc1cc2c(cc1OC)C=CC(C)(C)O2
Yield: 88 %

Procedure:
In 80 ml of anhydrous tetrahydrofurane 5.0 g (20 millimoles) of 6-methoxy-7-methoxy-2,2-dimethyl-4-chromanone are dissolved whereupon 1.5 g of lithium aluminum hydride are added in small portions under stirring and the reaction mixture is heated to boiling for an hour. The reaction mixture is worked up according to Example 31. The product is purified by column chromatography. Thus 4.1 g of the desired compound are obtained in the form of a colorless oil, yield 88%.
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1([CH3:10])[CH2:9][NH:8][CH2:7]1)=[O:5].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[CH3:25].[Li+].[OH-]>>[Cl:1][C:13]1[CH:18]=[CH:17][C:16]([NH:24][C@@H:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([CH3:25])[CH:15]=2)[C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=1[CH2:25][N:8]1[CH2:9][C:6]([CH3:10])([C:4]([OH:3])=[O:5])[CH2:7]1
Reactant: COC(=O)C1(C)CNC1
Reactant: Cl
Reactant: Cc1cc([C@H](N)C(F)(F)F)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc([C@H](Nc2ccc(Cl)c(CN3CC(C)(C(=O)O)C3)c2)C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to Scheme 4 following a procedure analogous to Example 61 using 3-methyl-azetidine-3-carboxylic acid methyl ester hydrochloride (INT 14) in step 1 and (S)-1-(4-chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethylamine hydrochloride in step 2, followed by a LiOH-mediated ester cleavage.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[NH2:14])[CH:8]=1)=[O:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[Cu](I)I.O>[C:13]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:15])[NH2:14]
Reactant: NC(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Reactant: Oc1ccc(F)cc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc(NC(=O)c2ccccc2Oc2ccc(F)cc2)c1
Reaction time: 0.25 h

Procedure:
To a mixture of 2-bromo-N-(3-carbamoylphenyl)benzamide (100 mg, 0.28 mmol), 4-fluorophenol (47.1 mg, 0.28 mmol), potassium phosphate (119 mg, 0.56 mmol), copper iodide (53 mg, 0.28 mmol) in a microwave vial was added 0.9 μL of DMF and 19 μL of water. The reaction was subjected to microwaves at 150° C. for 15 min. The reaction was cooled, the solids were filtered and the residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)benzamide. LC/MS: m/z 351.0 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[Cl:25]CCl.C([Li])CCC>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:25])=[N:17][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a mixture of 1-benzyloxy-4-(2-nitro-ethyl)-benzene described in Manufacturing Example 229-1-2 (39 g, 0.15 mol), tetrahydrofuran (350 mL) and dichloromethane (350 mL) was added n-butyl lithium (63 mL, 2.6 M n-hexane solution, 0.17 mol) at −78° C., which was stirred for 20 minutes at the same temperature. To the reaction mixture was added titanium (IV) chloride (25 mL, 0.23 mol) at the same temperature, and the mixture was warmed gradually to 10° C. After cooling the reaction mixture to 0° C., water (500 mL) and ethyl acetate (700 mL) were added, and the reaction mixture was warmed to room temperature. This organic layer was separated, washed with water (500 mL) and saturated sodium chloride water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. This residue was filtered with neutral silica gel (ethyl acetate:heptane=1:1), and this filtrate was concentrated under a reduced pressure. The obtained residue was washed with diethyl ether-heptane (1:10) to obtain the title compound (33 g, 78%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:46])[F:45])=[N:24]3)[CH2:30][CH2:31]2)[S:36][CH:37]=1)=[O:41]
Reactant: CNC1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (145 mg, 0.9 mmol) (prepared by the method described from Example 6, Step A) and triethylamine (0.16 mL, 1.13 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (316 mg, 0.75 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 60-100% of ethyl acetate in hexanes as eluant to give 242 mg of the title compound, a compound of the present invention as white foam.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:10]([C:7]1[S:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:16])=[CH:9][CH:8]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(=O)C(F)(F)F)s1
Reaction time: 1 h

Procedure:
To a stirred solution of D1 (1.0 eq) in THF (0.1 M) at RT was added a solution of LiOH (2.0 eq) in H2O (0.1 M) and the reaction mixture was stirred for 1 hr, then quenched by adding 6M HCl solution until pH=2. The organic solvent was evaporated and the product was extracted by DCM. Organic layers were washed with brine and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave the crude product which was purified by flash column chromatography using Pentane to yield the desired compound as a brown oil. 1H NMR (300 MHz, CDCl3, 300K) δ 7.85-7.80 (1H, m), 7.32 (1H, d, J=4.2 Hz), 3.66 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Fluoro-naphthalene-1-sulfonyl chloride 27 (10.0 g, 40.9 mmol) was dissolved in THF (100 mL) and stirred at room temperature. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (8.19 g, 40.9 mmol) and triethylamine (4.14 g, 5.75 mL, 40.9 mmol) were added and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo. Dichloromethane (250 mL) was added and the solution was charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 28 as a yellow foam. Wt.: 15.1 g (90%). 1H NMR (300 MHz, CDCl3) δ 8.62 (d, 1H), 8.26 (m, 2H), 7.69 (m, 2H), 7.20 (m, 1H), 4.92 (d, 1H), 3.82 (m, 2H), 3.26 (m, 1H), 2.70 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H), 1.24 (m, 2H); LC/MS m/z 409 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1([CH2:13][CH:14]([N:16]2[C:29]3[CH:28]=[C:27]([C:30](=[S:32])N)[CH:26]=[CH:25][C:24]=3[S:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:30]([C:27]1[CH:26]=[CH:25][C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:14]([CH3:15])[CH2:13][N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:29]=2[CH:28]=1)=[S:32]
Reactant: CC(C)CCN
Reactant: CC(CN1CCCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
3-Methylbutylamine (4.65 cc) is added to a solution of 10-[(2RS)-1-piperidino-2-propyl]-2-phenothiazinecarbothioamide (3.07 g) in absolute ethanol (65 cc). The mixture is brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is diluted with ethyl acetate (150 cc), the solution obtained is washed with distilled water (3×50 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa), and the residue is purified by chromatography on a column (height: 23.2 cm; diameter: 3.6 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (1 liter) and 50:50 (2 liters), collecting 60-cc fractions. Fractions 5 to 13 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give N-(3-methylbutyl)-10-[(2RS)-1-piperidino-2-propyl]-2-phenothiazinecarbothioamide (2.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 722.5 [(M+H)+]
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl.O>[CH3:15][C:4]1([CH3:16])[CH2:3][N:2]([N:1]2[CH2:25][CH2:26][CH2:27][C:28]2=[O:29])[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)CN(N)c2cc([N+](=O)[O-])ccc2O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN(N2CCCC2=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 0.5 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.35 g of 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine and the solution was cooled on an ice bath. To this solution was added 0.16 g of triethylamine followed by dropwise addition of a solution of 0.18 ml of 4-chlorobutyryl chloride in 1.4 ml of methylene chloride. After 30 minutes, the reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was crystallized from ether to give 0.43 g of crude crystals of 4-chloro-N-(3,4-dihydro-2,2-dimethyl-6-nitro- 2H-1,4-benzoxazin-4-yl)butyrylamide. The crude crystals were used without purification in the next reaction. (4) In 8 ml of N,N-dimethylformamide was dissolved 0.41 g of the above amide and the solution was cooled on an ice bath. Then, 0.14 g of potassium tert-butoxide was gradually added. The mixture was stirred with ice-cooling for 1 hour, after which it was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and crystallized from ether. The crude crystals were recrystallized from ethanol to give 0.16 g of 3,4-dihydro-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[N:35]1(C(N2C=CN=C2)=O)[CH:39]=CN=[CH:36]1.CNC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([N:35]([CH3:39])[CH3:36])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: CNC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N(C)C)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Dimethylamine (286 μL, 0.57 mmol) was added to the reaction mixture. The reaction vial was sealed and the mixture was heated at 70° C. for 2 hours. The mixture was cooled to ambient temperature. The DMF was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (10 mg). MS (ES+APCI) m/z=482 (M+H).