Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[CH2:12][C@@:11]2([CH3:14])[O:13][C@@:3]31[C@@H:15]1[C@@H:7]([N:8]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:9](=[O:16])[C@H:10]21)[O:6][CH2:5][CH2:4]3.Cl.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>N1C=CC=CC=1.CCOC(C)=O>[CH3:14][C@:11]12[O:13][C@:3]3([C@@H:15]4[C@@H:7]([N:8]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=5)[C:9](=[O:16])[C@H:10]14)[O:6][CH2:5][CH2:4]3)/[C:2](=[N:30]/[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)/[CH2:12]2
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reactant: NN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@]12C/C(=N\N3CCOCC3)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a stirring solution of Example 3 (85 mg, 0.216 mmol) in pyridine (2 mL) was added. N-aminomorpholine hydrochloride (0.287 mmol, 1.5 eq). The mixture was stirred at 50° C. for 1 h. The reaction was judged completed by LCMS. The reaction mixture was cooled to room temperature. It was then diluted with EtOAc (6 ml) and extracted with 1N HCl (2×10 ml). The ethyl acetate layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on Isco (12 g column) 0-5% MeOH-DCM to give Example 92 (59 mg, 58%, 0.133 mmol).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:38]1N=CN=C(N)C=1OCC>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][CH3:38])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: CCOc1c(N)ncnc1Cl
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine using 6-Chloro-5-ethoxy-pyrimidin-4-ylamine instead of 6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=517, obsd.=517).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:18][CH:19]=2)[CH2:7]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide (1.74 g, 3.05 mmol) was dissolved in methylene chloride (5.0 mL) and trifluoroacetic acid (5.0 mL, 26 mmol) and stirred at room temperature After 4 hours, LC/MS data indicated that the reaction was complete and the desired product was formed (LCMS (M+H)+: m/z=471.3). The volatiles were removed in vacuo and the residue was azeotropically washed with acetonitrile several times (4×10 mL) to remove the excess TFA. The residue was dissolved in methanol (15 mL) and to this was added 14.8 M ammonium hydroxide in H2O (3.0 mL, 44 mmol) and ethylenediamine (0.10 mL, 1.5 mmol) and the resulting solution was stirred at room temperature for 3 hours to afford the desired product. The product was further precipitated out as a white solid by the addition of H2O (15 mL) and the heterogeneous solution was stirred for 30 minutes prior to pouring into water (60 mL). The precipitate was filtered off, washed with water (2×10 mL), and dried under high vacuum to afford the desired product (1.05 g, 78% yield). LCMS (M+H)+: m/z=441.1. 1H NMR (400 MHz, CD3OD): δ 8.78 (s, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=4.0 Hz, 1H), 7.00 (d, =4.0 Hz, 1H), 6.64 (t, J=8.5 Hz, 2H), 4.55 (d, J=8.0 Hz, 2H), 4.40 (d, J=8.0 Hz, 2H), 4.19 (m, 1H), 3.62 (s, 2H), 1.22 (d, J=7.0 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([C:4]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccccc4Cl)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2-chlorobenzenesulfonyl chloride (78 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.69 (m, 2H), 7.57 (m, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.12 (br s, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.77 (br d, J=12.0 Hz, 2H), 2.75 (t, J=10.8 Hz, 2H), 2.06 (s, 1H), 1.84 (d, J=10.8 Hz, 2H), 1.31 (m, 2H). MS m/z (ESI) 448 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]([O:24]C)=[O:23])=[CH:12]1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCOCC1.O>[C:4]([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]([OH:24])=[O:23])=[CH:12]1)([CH3:6])([CH3:7])[CH3:5]
Reactant: COC(=O)[C@H](Cc1cn(CC(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Lithium hydroxide monohydrate (0.455 g, 10.84 mmol) was added to a solution of (S)-methyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 10.84 mmol) in dioxane (50 mL) and water (16.67 mL) and stirred at RT for 1 hr. The reaction was neutralized with 1M HCl and extracted with EtOAc. The organic layer washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified via silica gel chromatography (120 g column, 0-50% EtOAc:Hex over 20 CV) to get the product (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.54 g, 78% yield). 1H NMR (400 MHz, chloroform-d) d 7.62 (d, J=7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.15 (ddd, J=7.9, 5.6, 2.3 Hz, 1H), 6.99 (s, 1H), 5.08 (d, J=7.8 Hz, 1H), 4.71 (s, 2H), 4.65 (br. s., 1H), 3.42-3.31 (m, 2H), 1.46 (s, 18H). ESI-MS(+) m/z=441 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccccc1)c(OCc1ccccc1)c2=O
Temperature: 90 °C
Yield: 90.8 %

Procedure:
Intermediate 174, N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.266 mmol) in a mixture of acetonitrile (10 ml) and water (10 ml) was treated with phenylboronic acid (0.042 g, 0.35 mmol), sodium carbonate (0.062 g, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.124 g (91% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.61 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.49 (2H, d, J=6.1 Hz, NCH2), 7.02 (2H, m, aromatics), 7.29–7.51 (12H, m, aromatics and NH). HRMS (ESI+) calculated for C30H29FN3O4 [M+H+]: 514.2142. found: 514.2137.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12](I)=[CH:11][N:10]=[C:9]([NH2:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[N:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1>>[CH:1]1([NH:6][C:7]2[C:12]([C:21]3[CH:20]=[C:19]([Cl:22])[N:18]=[N:17][C:16]=3[Cl:15])=[CH:11][N:10]=[C:9]([NH2:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc(I)c(NC2CCCC2)n1
Reactant: Clc1ccc(Cl)nn1
Product: Nc1ncc(-c2cc(Cl)nnc2Cl)c(NC2CCCC2)n1

Procedure:
Compound 323 was prepared from compound 243 and 3,6-dichloropyridazine using chemistry similar to that described in example 200. LCMS-ESI (POS), M/Z, M+1: Found 325.0.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28](O)[CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:26]1[CH:25]=[C:24]([F:23])[CH:29]=[CH:28][C:27]=1[N+:31]([O-:33])=[O:32])[CH3:2]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml) was added a solution of triphenylphosphine (13 g) and 5-fluoro-2-nitrophenol (10 g) in tetrahydrofuran (65 ml). To this solution was added diethyl azodicarboxylate (10 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure and diisopropyl ether was added. The precipitated crystals were collected by filtration and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give a yellow oil. To this oil was added ethyl acetate, washed with an aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.6 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[F:13])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: N#Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2cnc(Cl)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Preparation 17, 1-chloro-4-hydroxyisoquinoline and 3,4-difluorobenzonitrile were converted to the title compound: RT=3.90 min; m/z (ES+)=299.04 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:22]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:24][CH2:23]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Reactant: NC(=O)CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: NC(=O)CCN1CCN(C2Cc3cc(Cl)ccc3Sc3cc(F)ccc32)CC1
Reaction time: 8 h

Procedure:
A mixture of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo(b,f)-thiepin (2.8 g), 3-(1-piperazinyl)propionamide (3.2 g) and chloroform (10 ml) is refluxed with stirring for 8 hours. The solvent is than evaporated under reduced pressure, and the residue is extracted by shaking with a two-phase system consisting of benzene (30 ml) and a solution of methanesulfonic acid (4 g) in water (50 ml). The clear aqueous solution is separated and then made alkaline with aqueous ammonia (10 ml). The so-formed suspension of the amorphous base is diluted with ethanol (100 ml), and the mixture is briefly warmed to boiling. The resultant clear solution is then allowed to crystallize at room temperature for 6 hours. The crystalline product is separated, washed with a small amount of ethanol, and then dried in vacuo. The obtained base (2.35 g, 60% of theory) melts at 179°-182° C.; it can be purified by crystallization from ethanol to give the title compound having a m.p. of 182°-184° C. and which is identical with the product of the preceding example 1.
Reaction SMILES: Cl.[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:5]=1)[CH3:3].[C:28]12[C:36](=[O:37])[O:35][C:33](=[O:34])[C:29]=1[CH2:30][CH2:31][CH2:32]2.O>CN(C)C=O>[CH2:2]([C:4]1[S:8][C:7](=[N:9][C:36]([C:28]2[CH2:32][CH2:31][CH2:30][C:29]=2[C:33]([OH:35])=[O:34])=[O:37])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:15][CH:16]=2)[N:5]=1)[CH3:3]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.8 %

Procedure:
To a solution of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline hydrochloride (200 mg) in N,N-dimethylformamide (3 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (100 mg), and they were stirred at room temperature for 3 days. To the reaction mixture was added water (20 ml), and powders so precipitated were collected by filtration. The powders were washed successively with water, ethanol and diethyl ether and then dried, whereby 160 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([F:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:29](=[O:35])[CH2:28][S:27]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:28]4/[C:29](=[O:35])[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:26](=[O:25])[S:27]/4)=[CH:13][CH:14]=3)[C:9]([F:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(F)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethyl-benzyl)-3-fluoro-1H-indazole-5-carbaldehyde (from Example 368) and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.
Reaction SMILES: [CH2:1]1[O:16][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][CH:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:8][CH2:9]2)[O:16][CH2:1]1
Reactant: C1=C(c2cccnc2)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1cncc(C2CCC3(CC2)OCCO3)c1
Reaction time: 24 h

Procedure:
A mixture of 4-(3-pyridyl)cyclohex-3-en-1-one ethylene ketal prepared above (26 g, 120.0 mmol) in EtOAc (240 mL), containing 10% Pd/C (3.9 g), was hydrogenated under atmospheric pressure for 24 h. At this time, an additional 1.3 g of 10% Pd/C was added and the mixture allowed to stir an additional 2.5 d under an atmosphere of hydrogen gas. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford crude 4-(3-pyridyl)cyclohexanone ethylene ketal, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:36]1([CH2:42][CH2:43][CH2:44]O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:44][CH2:43][CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Reactant: OCCCN1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(OCCCN3CCCCC3)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 3-piperidin-1-yl-propan-1-ol and 0.68 ml (0.004 mmol) of di-tert.-butyl azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 0.600 g (93%) of the title compound as white solid. MS (m/e): 343.3 (M+H)+.
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:11][O:12][C:13](=[O:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].C(O)(=O)C.[Br:25]Br>O>[CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:11][O:12][C:13](=[O:15])[C:14]=2[Br:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c[n+](CCSC2CCCCC2)[n-]o1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1o[n-][n+](CCSC2CCCCC2)c1Br
Reaction time: 0.5 h

Procedure:
4 Parts of 3-[2-(cyclohexylthio)ethyl]sydnone is stirred with 4 parts of potassium acetate in 40 parts by volume of acetic acid while 2.8 parts of bromine in 10 parts by volume of acetic acid is added dropwise. Stirring is continued for 30 minutes and then the reaction mixture is poured into water, filtered and washed with water to give 3-[2-(cyclohexylthio)ethyl]-4-bromosydnone.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1.[C:23](=[O:26])([O-])O.[Na+]>C1COCC1>[CH2:23]([O:26][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1)[C:11]1[CH:20]=[CH:19][CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.85 mL (3.85 mmol) sodium benzylate solution (1M in benzylalcohol) were added to 1.24 g (3.85 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 50 mL THF and stirred overnight at RT. The reaction mixture was combined with saturated sodium hydrogen carbonate solution and extracted with EtOAc. The combined organic phases were dried and evaporated down i. vac.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([Cl:14])[C:9]([F:13])=[CH:10][CH:11]=2)[C:6](=[O:15])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C(=O)(O)[O-].[Na+]>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([Cl:14])[C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([O:15][CH3:22])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)c2c1ccc(F)c2Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1cn(C(C)=O)c2ccc(F)c(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 2 g of 1-acetyl-4-chloro-5-fluoroindolin-3-one, 2 g of powdered sodium hydroxide and 30 ml of dimethyl sulfate was stirred at room temperature for 5 hours. After the addition of 250 ml of saturated sodium bicarbonate solution the mixture was stirred overnight and subsequently filtered. The residue was filtered in 150 ml of ether and 100 ml of ethyl acetate. The solution was dried over sodium sulfate, filtered and evaporated. There were obtained 2 g (95%) of 1-acetyl-4-chloro-5-fluoro-3-methoxyindole as greenish crystals with m.p. 114°-115°.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)(CC)C.CO>[C:2]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cc[n+](CCc2c[nH]c3ccccc23)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CO
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1

Procedure:
A suspension of 4-benzamido-1-[2-(3-indolyl)ethyl]-pyridinium bromide (10.5g) and sodium borohydride (2.8 g) in sec-butanol (100 ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled to 25° and diluted with aqueous methanol. The product was separated by filtration and washed with aqueous methanol then with water and finally with methanol, and dried to give the crude title compound. This was purified as described in Example 5 to give the title compound mp 203°-5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-])=[O:16])=[CH:13][CH:12]=1)=[O:8])([O-:3])=[O:2].O.[NH2:24][NH2:25]>CCO>[NH:24]([C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:20]=[CH:21][CH:22]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:12][CH:13]=1)=[O:16])[NH2:25]
Reactant: O=C([O-])c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a suspension of 4-{[(3-nitrobenzoyl)amino]methyl}benzoate (500 mg, 1.59 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.16 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×2 mL), EtOH/water (2×2 mL)and water (2×2 mL), and drying under vacuo at 70° C. for 5 hrs gave 379 mg of the title compound (76%) as a pale yellow solid in 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).