Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][NH:39][CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:44]([BH3-])#N.[Na+]>CC#N.CO>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][N:39]([CH3:44])[CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCNC3)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCN(C)C3)c2)cc1

Procedure:
The product from Example 93D (0.030 g, 0.0525 mmoles) in 1:1 CH3CN/MeOH (2 mL) was treated with 37% aqueous formaldehyde (0.020 mL, 0.263 mmoles) and sodium cyanoborohydride (0.008 g, 0.131 mmoles). Reaction mixed overnight at room temperature. Reaction quenched with two drops acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TRIFLUOROACETIC ACID in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (500 MHz, DMSO) δ8.96 (s, 1 H), 7.25 (m, 7 H), 7.20 (m, 1 H), 7.05 (m, 1 H), 6.97 (d, 2 H), 6.92 (d, 2 H), 6.70 (m, 1 H), 6.56 (dd, 1 H), 6.53 (dd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.95 (m, 1 H), 3.50-3.80 (m, 1 H), 3.30-3.50 (m, 1 H), 3.00-3.20 (m, 2 H), 2.92 (s, 3 H), 2.80 (m, 5 H), 2.40 (s, 3 H), 2.00-2.30 (m, 1 H), 1.80 (m, 1 H); MS (ESI+) m/z 586 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=O)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[O:20][N:19]=[C:2]([C:3]3[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(N)=NO)cc1F
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(NCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 50 (141.65 mg; 0.50 mmol) and Intermediate 3 (135.76 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method B): 474.4 (M+H)+. HPLC (Method A) Rt 6.70 min (Purity: 84.4%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1)([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(c1ccc(-n2ccnc2Sc2ccccc2[N+](=O)[O-])cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Sc1nccn1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To the mixture of conc. hydrochloric acid (3.2 ml) and ethanol (2 ml) is added 1-[1-{4-[2-(2-nitrophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2.0 g), and thereto is added dropwise a solution of stannous chloride dihydrate (2.7 g) in ethanol (4 ml) at a temperature below 25° C. with water-cooling, and the mixture is stirred at room temperature for two hours. The mixture is poured into ice-water and basified with aqueous sodium hydroxide solution, extracted with chloroform, washed with water, and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; chloroform: methanol=50:1-25:1), and further dissolved in methanol. The mixture is added dropwise with stirring into water (about 40 ml) and the resulting precipitates are collected by filtration and dried to give 1-[1-{4-[2-(2-aminophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (1.6 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:8]
Reactant: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Oc4cccc(OC(F)(F)F)c4)C3)CC2)cc1
Yield: 99.3 %

Procedure:
The title compound (D189) (39 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-fluoro-2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)nicotinic acid (D134) (27 mg, 0.072 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (16.5 mg, 0.072 mmol).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OCc4ccccc4)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@H](OCc2ccccc2)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 75.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,5S*)-5-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (94.3 mg, 0.134 mmol) prepared in Example 113a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (56.0 mg, 75%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][C:39]([Cl:38])=[CH:40][CH:41]=3)=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3-(4-Amino-2-phenylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and triethylamine (1 mL) were combined in CH2Cl2 (10 mL). 4-Chlorobenzoyl chloride (0.29 mL, 2.3 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:26]1([C:2]2[N:3]=[C:4]([N:19]3[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([N:12]4[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]4)[C:6]=3[N:7]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCS(=O)CC4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N4CCS(=O)CC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-4,8-bis-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 295°-297° C.) and piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:15][N:14]3[CH2:13][CH2:12][CH:11]([C:6]1=2)[CH2:17][CH2:16]3
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccccc1F
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2F)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (158 mg, 0.70 mmol; Example 2B) and 1-fluoro-2-vinylbenzene (171 mg, 1.40 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.63-1.76 (m, 2H), 1.87-2.01 (m, 2H), 2.39 (s, 3H), 2.88-3.22 (m, 7H), 4.16 (s, 2H), 4.33 (t, J=7 Hz, 2H), 6.86-7.26 (m, 7H); MS (DCI/NH3) m/z 349 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.4 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.34 g, 1.33 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 7 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-ylpiperidin-4-ol as a colourless oil (0.194 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 3.75-3.68 (m, 1H); 3.67-3.51 (m, 4H); 3.25-3.17 (m, 1H); 2.66-2.56 (m, 3H); 2.03-1.84 (m, 5H); 1.65-1.53 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH2:10][OH:11].C(O)(=O)C.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:3]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:10][OH:11])[CH:4]=1
Reactant: CC(C)(C)C=O
Reactant: Nc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CNc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethanol (4.44 g) in methanol (50 ml) were added acetic acid (1.4 ml) and pivalaldehyde (2.0 g). The mixture was stirred for 30 minutes at room temperature. To the solution was added sodium cyano borohydride (1.5 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was then processed in substantially the same manner as in Example 52-(7) to give 5.5 g of an oily compound.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:3]#[C:2][C:1]([NH2:5])=[O:4])[CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: C#CC(N)=O
Reactant: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C#Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 15 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was triturated with hot MeOH and then triturated with hot EtOAc to give the title compound as a light tan solid (107.4 mg, 74%). 1H NMR (DSMO-d6) δ: 9.33 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.60 (dd, J=7.3, 2.1 Hz, 1H), 8.17 (br. s., 1H), 7.87 (s, 1H), 7.67 (br. s., 1H), 7.37-7.55 (m, 4H), 7.17-7.25 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[N:14]O)[CH2:12][S:11](=[O:17])(=[O:16])[N:10]([CH3:18])[C:9]=2[CH:19]=1)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:13]([NH2:14])[CH2:12][S:11](=[O:17])(=[O:16])[N:10]([CH3:18])[C:9]=2[CH:19]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2N

Procedure:
4-Hydroxyimino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (1.50 g, 5.28 mmol) was hydrogenated over Pd(OH)2 (1.30 g, 20% on carbon, wet) in MeOH (100 mL) for 60 h. After filtration and evaporation, chromatography (silica, 0-3% MeOH in CH2CL2) furnished the title compound. MS (+APCI, m/z): 271 (M+H)+, 254 (M−NH2)+, MS (-APCI, m/z): 252 (M−N4)−.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:31]=[CH:32][CH:33]=[C:17]([F:16])[CH:18]=4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Oc1cccc(F)c1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1cccc(F)c1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (140 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (240 mg, 0.86 mmol, Amine-40, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:50][C:49]2[CH:51]=[CH:52][C:46]([Cl:45])=[CH:47][CH:48]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (1 g; 3.48 mmol) is suspended in acetonitrile (7 ml) and N,N-diisopropyl ethyl amin (1.22 ml; 6.96 mmol) is added at 25° C. BOP-Cl (1.772 g; 6.96 mmol) is added as a solid and after stirring for 30 min at 25° C. 4-chloroaniline (0.444 g; 3.48 mmol) is added to the reaction mixture. The mixture is stirred for 18 h at 25° C., evaporated to dryness and dissolved in ethyl acetate (100 ml). The organic phase is washed with saturated aquous Na2CO3 solution (100 ml), 2 N HCl (50 ml), water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 0.5 g (36.2%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCC(CO)CC2)nc1
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A mixture of 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (55 mg, 0.129 mmol), piperidin-4-yl methanol (22.3 mg, 0.194 mmol), triethylamine (0.036 mL, 258 mmol), and DMF (2 mL) was heated in a sealed tube at 140° C. for 5 hr. The crude material was purified by reverse phase chromatography (10% acetonitrile-water ramped to 60% acetonitrile-water). The product 4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (25 mg, 38%) was isolated as a light yellow solid. MS calcd. for C28H26F2N4O3 [(M+H)+] 505.2, obsd. 505.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](N)=[O:5].C12C(=CC=CC=1)NC(=O)[O:20][C:18]2=[O:19].[N+]([O-])(O)=O.OS(O)(=O)=O.O=S(=O)=O.S(=O)(=O)=O>>[N+:11]([C:10]1[CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[C:3]2[C:4]([O:20][C:18](=[O:19])[NH:1][C:2]=12)=[O:5])([O-:13])=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O=[N+]([O-])O
Product: O=c1[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2c(=O)o1

Procedure:
A process for the manufacture of 2-amino-3,5-dinitrobenzamide which comprises nitrating at -20° C. to 80° C. isatoic anhydride dissolved in an inert organic solvent with an acid mixture consisting of 85-100% strength nitric acid and oleum, said acid mixture containing 0.5 to 20 moles of sulfur trioxide per mole of nitric acid, to produce 3,5-dinitroisatoic anhydride, allowing the reaction mixture to separate into an organic phase and an acid phase containing the 3,5-dinitroisatoic anhydride, adding 20-30% strength aqueous ammonia to the resultant acid phase in an amount of 9 to 25 moles of ammonia per mol of isatoic anhydride, and reacting the ammonia and the acid phase to produce a high yield of 2-amino-3,5-dinitrobenzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>C(O)(C)C>[CH3:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=1)=[N:3][CH:4]=[CH:5]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Temperature: 180 °C
Yield: 81.1 %

Procedure:
1-Chloro-6-methyl-5-nitroisoquinoline (0.25 g, 1.1 mmol) and 3-(trifluoromethyl)benzenamine (0.17 mL, 1.3 mmol) were added to a microwave tube containing 3 mL of isopropanol. The tube was capped and heated at 180° C. for 1500 seconds. The volatiles were removed in vacuo. The residue was taken up in DCM and washed with saturated NaHCO3. The organic layer was dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 10 to 40% of ethyl acetate in hexanes to give the product as an orange solid (0.31 g, 79%). MS (M+H)+348.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[C@@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21].Cl.O1CCOCC1>O>[CH3:16][C@@:10]12[C:13]([CH3:14])([CH3:15])[C@@H:7]([C:6]3[C:4](=[O:5])[N:20]([CH2:19][C:18]([F:23])([F:22])[F:17])[NH:21][C:11]=31)[CH2:8][CH2:9]2
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Temperature: 100 °C
Yield: 17 %

Procedure:
A mixture of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (Intermediate 4; 5.00 g, 22.3 mmol) and 2,2,2-trifluoroethylhydrazine (70% in water; Aldrich; 25.00 g, 153 mmol) was heated in a sealed tube at 100° C. for 19 h. The reaction mixture was allowed to cool, and HCl in dioxane (4 M; 40 mL, 160 mmol) was added cautiously. The reaction mixture was heated again at 100° C. for 45 min, cooled to room temperature, and added to water (200 mL). The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, evaporated, purified by flash chromatography (20-50% ethyl acetate) to give (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.04 g, 17%) as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10]([O:12]CC)=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10]([OH:12])=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.1 %

Procedure:
A suspension of ethyl 2-bromoimidazo[5,1-b] thiazole-7-carboxylate (49.5 g, 200 mmol) in methanol (720 ml) was cooled in a brine/ice water bath. A 2.7 M aqueous solution (720 ml) of sodium hydroxide was added to this suspension, and the mixture was stirred at room temperature for about 15 hr. After the completion of the reaction, methanol was removed by distillation under the reduced pressure for concentration, and the concentrate was cooled in a brine/ice water bath. Concentrated hydrochloric acid (164 ml) was added to this concentrate, and the mixture was adjusted to pH 5 and was stirred at room temperature overnight. The resultant precipitate was collected by filtration. The precipitate was then washed with water (60 ml) and was dried under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (46.5 g, yield 94.0%) as a white solid.