Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([O:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[C:17]=3[CH:35]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CO.O>[CH:4]1([O:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[C:17]=3[CH:35]=2)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 12 h
Yield: 67.4 %

Procedure:
Lithium hydroxide monohydrate (0.267 g.) was added as a solid to a stirred solution of methyl 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoate (0.7 g.) in methanol (15 ml.) and water (2 ml.). The mixture was stirred for 12 hours then diluted with water and acidified to pH 3.35 with 3M hydrochloric acid. The precipitate which formed was isolated by filtration, washed with water and crystallized from methanol to give the title compound as a solid (0.457 g., 67%), m.p. 221°-222° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH:11]C=O)[C:4]=2[CH:3]=1.[ClH:14]>>[ClH:14].[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:4]=2[CH:3]=1
Reactant: O=CNC1CCCc2sc(Br)cc21
Agent: Cl
Product: NC1CCCc2sc(Br)cc21

Procedure:
Acid hydrolysis of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thien-4-amine (Example 35) with 1 N hydrochloric acid after refluxing for one hour and evaporating to dryness affords 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C(O)(=O)C>[Cl:1][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH3:9])[C:19]=1[CH3:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2ccccc2cc1C
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(Cl)c1C

Procedure:
N-Chlorosuccinimide (14 g) in glacial acetic acid (150 ml) was added to 2,3-dimethylnaphthalene (15.6 g) in refluxing glacial acetic acid (150 ml) over 30 min. The solution was evaporated to dryness and the residue was washed with ether (3 × 100 ml) and insoluble material discarded. The ether washings were evaporated and the residue recrystallised from ethanol to give 1-chloro-2,3-dimethylnaphthalene (1) m.p. 55°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:13][CH2:12][CH2:11][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:13](=[O:19])[CH2:12][CH2:11][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=NOCCS2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S1CCON=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-Dihydro-3-(3-fluorophenyl)-1,4,2-oxathiazine (19.7 g, 0.1 mol) was dissolved in chloroform, 50 ml). 3-Chloroperoxybenzoic acid (21 g) dissolved in chloroform (200 ml) was added dropwise at such a rate that the temperature of the reaction mixture remained at between 25° to 30° C. After the addition was complete, the reaction was left stirring at room temperature overnight. Saturated aqueous sodium bicarbonate was added and stirred until all gassing ceased. The chloroform solution was washed with water, dried over anhydrous magnesium sulphate and evaporated to leave a solid which was recrystallised from ether/ligroin, to give 5,6-dihydro-3-(3-fluorophenyl)-1,4,2-oxathiazine 4-oxide, mp 79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare according to the method of example 11.1 using 3,4-dichlorophenylacetonitrile (50 mmol) and 2-(3-bromo-propoxy)-tetrahydro-pyran (50 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([Cl:15])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccc1C

Procedure:
A mixture of 10.0 g (60.17 mmol) of 3-methoxy-4-methylbenzoic acid, 15 ml (210 mmol) of thionyl chloride and 10 ml of toluene was stirred at reflux for 2 hours. The solvents were then evaporated and the residue was distilled bulb-to-bulb at 60°-70° C. at a pressure of 0.04 mm of Hg to give the title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH2:12]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:12][CH3:11])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc(Br)c(OC)n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 85.6 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3 g, 13.4 mmol) and methylamine (2 M in THF, 50 mL, 100 mmol) in THF (20 mL) was stirred for 40 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 1:1) to afford 2.5 g of the title compound. tR: 0.81 min (LC-MS 2); ESI-MS: 218/220.1 [M+H]+ (LC-MS 2); Rf: 0.39 (hexane/EtOAc 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:22])[CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][O:22][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: OCCCCO
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,4-butanediol under conditions shown in Table 19, ethyl N-{2-(4-hydroxybutoxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[O:12].OC1C=CC(N[S:48]([CH3:51])(=[O:50])=[O:49])=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner to that described in Example 45, Step 4) (0.140 g, 0.239 mmol) in DCM (5 ml), a solution of N-(4-hydroxyphenyl)-methanesulfonamide (0.0672 g, 0.359 mmol) and DMAP (0.0438 g, 0.359 mmol) in DCM (5 ml) was added drop wise, and the reaction was stirred at RT for 3 hours. The solvent was evaporated and the resulting crude was purified by chromatography on silica gel column (DCM:MeOH=10:0.4). A second purification by crystallization from absolute ethanol was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(methylsulfonamido)-phenoxy)carbonyloxy)ethyl)pyridine 1-oxide as a brown solid (0.050 g, 0.079 mmol, 33% yield, MS/ESI+ 632.74 [MH]+, [αD]=−36.59, c=0.252, DCM).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.ClC1C=[C:21](C)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)N=1>>[CH3:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:3]=[C:8]([CH3:7])[N:9]=[C:21]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:20]=2)[CH2:29][CH2:28]1)(=[O:31])=[O:32]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Cl)nc(N2CCN(S(C)(=O)=O)CC2)n1
Product: COc1cc(Nc2nc(C)cc(N3CCN(S(C)(=O)=O)CC3)n2)ccc1-n1cnc(C)c1
Yield: 4 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-chloro-2-(4-methanesulfonyl-piperazin-1-yl)-6-methyl-pyrimidine. The title compound was isolated as a yellowish solid in a yield of 4%. MS ISP (m/e): 458.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.32 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.01 (s, 1H), 6.28 (s, 1H), 3.78 (s, 3H), 3.80-3.70 (m, 4H), 3.19 (t, 4H), 2.91 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:26][O:27][CH3:28])[C:21]2[S:22][CH:23]=[CH:24][N:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[NH2:35][NH2:36]>C(O)C>[Cl:1][C:2]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:26][O:27][CH3:28])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[NH:35][N:36]=1
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C=CC(=O)CCCOc2ccc(Cl)cc2Cl)cc1
Reactant: NN
Solvent: CCO
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C2CC(CCCOc3ccc(Cl)cc3Cl)=NN2)cc1

Procedure:
4-[6-(2,4-Dichloro-phenoxy)-3-oxo-hex-1-enyl]-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.259 mmol) and hydrazine (2 mL) was heated to 80° C. in ethanol (15 mL) for 2 h. The solution was concentrated in vacuo. The crude 4-{5-[3-(2,4-dichloro-phenoxy)-propyl]-3,4-dihydro-2H-pyrazol-3-yl}-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[N:22]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][N:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:24])[N:22]=1
Reactant: NNC(=O)c1csc(COc2ccccc2Cl)n1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1csc(COc2ccccc2Cl)n1
Temperature: 100 °C
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[(2-chlorophenoxy)methyl]-1,3-thiazole-4-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 47 mg of the title compound (79%) as a orange powder in 98.2% purity by HPLC (Rt: 5.07, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.Cl[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]2[CH:20]=[C:21]([C:26]3([O:32][CH3:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([F:25])[CH:24]=2)=[CH:14][CH:13]=1)[CH3:11]>>[F:25][C:23]1[CH:22]=[C:21]([C:26]2([O:32][CH3:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:20]=[C:19]([S:18][C:15]2[CH:14]=[CH:13][C:12]([CH:10]([O:8][N:7]=[C:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH3:11])=[CH:17][CH:16]=2)[CH:24]=1
Reactant: ON=C1CCOCC1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C4CCOCC4)cc3)c2)CCOCC1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 1, tetrahydropyran-4-one oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give tetrahydropyran-4-one O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl}oxime as an oil in 74% yield.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].[CH3:25][C:26]([CH3:28])=O>ClCCl>[CH:26]([NH:24][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[CH3:15])([CH3:28])[CH3:25]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (4.5 g, 21.2 mmol) was added portionwise to a solution of 1-methyl-1-phenylethylamine (0.96 g, 7.1 mmol) in a mixture of acetone (5 ml) and dichloromethane (120 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between aqueous sodium hydroxide solution (2M, 100 ml) and ethyl acetate (200 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml) and then dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give the title compound (1 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1.C(O)(C(F)(F)F)=O>C(O)CCC>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=2)[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c(F)cc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CNc1nc(Nc2cc(F)c(C#N)cc2OC)ncc1C(F)(F)F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-2-fluoro-5-methoxybenzonitrile (66 mg, 0.40 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in 1-butanol (2 mL) was added TFA (0.05 mL, 0.07 mmol). The reaction was stirred in a sealed tube at 75° C. for 2 h. The reaction was concentrated and the product was isolated by reverse-phase HPLC to give 2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=13.4, 2H), 8.34 (s, 1H), 8.29 (d, J=6.1, 1H), 7.56-7.42 (m, 3H), 3.93 (s, 3H), 2.95 (s, 3H); LRRK2 Ki=0.022.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2cccnc2c1O
Product: N#Cc1cnc2cccnc2c1Cl
Yield: 28.5 %

Procedure:
A solution of 4-hydroxyl-[1.5]naphthyridine-3-carbonitrile (1.0 g, mmol) in 20 ml POCl3 was refluxed for 3 hrs. After cooling, the solvent was removed by rotary evaporation. The residue was treated with ice-water mixture, made basic by NH4OH, and extracted with CH2Cl2. Removal of the solvent gave 4-chloro-[1.5]naphthyridine-3-carbonitrile (285 mg, 28.5%). This was heated at reflux with 3-bromoaniline (3 eq) in the presence of pyridine HCl salt (350 mg) in ethoxyethanol for 3 hrs under argon. After cooling, the solvent was removed by rotary evaporation. The residue was partitioned between ice-water and ethyl acetate, made basic with (NH4OH), extracted with ethyl acetate. The combined extracts were washed (brine) and dried (Na2SO4), and concentrated. The residue was triturated with ether. The title compound was collected and washed with ether, and dried. mass spectrum (electrospray, m/e): 326.9 (M+H); IR cm-1: 3372, 2209; H-NMR δ(DMSO-d6): 7.36-7.90 (3H, m, C4′ C5′-H and C6′ Hs in bromoaniline), 7.64 (1H, s, C2′-H), 7.94 (1H, dd, C7-H), 8.36 (1H, dd, C8-H), 8.66 (1H, s, C2-H), 8.98 (1H, dd, C6-H), 10.47 (1H, bs, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(methylsulfonamidomethyl)-phenylcarbamate (67 mg, 0.198 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (53 mg, 0.198 mmol) in acetonitrile were added 4-dimethylaminopyridine (24 mg, 0.198 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Fluoro-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 27) (72 mg) was obtained as 72% yield.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CSc2ccccc21
Temperature: 40 °C
Reaction time: 120 h
Yield: 40.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl)-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.093 g, 0.269 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.054 g, 0.323 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (108LM51-48) (0.042 g, 40%). 1H NMR (CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 4.18-4.10 (m, 2H), 3.38 (s, CH2), 3.15-3.00 (m, 2H), 2.30-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.75 (m, 3H), 1.60-1.40 (m, 5H), 1.40-1.15 (m, 8H), 0.90-0.82 (m, 6H); 13C NMR (CDCl3) δ 166.1, 139.2, 128.7, 127.2, 124.7, 123.5, 119.1, 61.4, 60.1, 57.3, 47.6, 38.3, 36.9, 32.1, 31.2, 29.9, 29.4, 28.2, 27.2, 26.5, 23.1, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=387.3.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31]>C(O)C.C(OCC)(=O)C>[CH2:20]([N:12]([CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][S:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])=[CH:3][C:4]1=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:21]
Reactant: CCN(CCN1CCSc2ccc(N)cc21)C(=O)OC(C)(C)C
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 2-(6-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(ethyl)carbamate (800 mg, 2.371 mmol) in ethanol (8 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.014 g, 3.56 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:1 hexanes:ethyl acetate giving the desired product (415 mg, 39.2%). 1H NMR (DMSO-d6) δ 7.70 (d, J=3.0 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.49-7.44 (m, 1H), 7.07 (t, J=4.4 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.35-6.26 (m, 2H), 6.08 (d, J=7.5 Hz, 1H), 3.64-3.49 (m, 2H), 3.45-3.25 (m, 4H), 3.24-3.12 (m, 2H), 3.01-2.85 (m, 2H), 1.39-1.29 (m, 9H), 1.02 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 447 (MH+, 100).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=O)[CH:3]=1.[CH2:16]([NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)[CH3:17]>>[CH2:16]([NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:14][C:4]3[CH:3]=[C:2]([OH:1])[C:7]4[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=4[CH:5]=3)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1)[CH3:17]
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc(O)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 359A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 3H) 1.37 (d, J=6.82 Hz, 3H) 2.90-3.13 (m, 4H) 3.13-3.24 (m, 2H) 3.33 (br. s., 2H) 3.92 (d, J=12.63 Hz, 2H) 4.16 (br. s., 2H) 4.57 (q, J=6.65 Hz, 1H) 6.43 (d, J=1.77 Hz, 1H) 6.57 (d, J=1.52 Hz, 1H) 6.94 (d, J=8.84 Hz, 2H) 7.70 (d, J=8.84 Hz, 2H) 8.18 (t, J=5.43 Hz, 1H) 9.66 (d, J=9.35 Hz, 1H) 10.75 (s, 1H). ESI-MS: m/z 425.4 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])[CH:18]=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=1)=[O:13].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(Cl)Cl>C(O)(C)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:27]([F:29])([F:30])[F:28])[CH:18]=[C:19]([NH:21][S:22]([CH2:25][CH2:26][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:24])=[O:23])[CH:20]=1)=[O:13]
Reactant: C=CS(=O)(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Reactant: C1CCNCC1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1cc(NS(=O)(=O)CCN2CCCCC2)cc(C(F)(F)F)c1)c1c[nH]c2ccccc2c1=O
Temperature: 75 °C

Procedure:
A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μL, 1.6 eq) and LiClO4 (20 mg, 1.7 eq) was suspended in a 1:1 solution of CH2Cl2:isopropanol (1.5 mL). The mixture was refluxed at 75° C. for 18 h. After this time, LCMS analysis showed >95% conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25%). 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, J=8.1 Hz, 1H), 8.05 (br s, 1H), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.66 (t, J=8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 481.1 m/z (MH+).