Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].CO>[Pd].C1COCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:10])[CH2:16][CH2:15]2)=[N:18][C:19]=1[CH3:26]
Reactant: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1N
Temperature: 26 °C
Reaction time: 0.5 h

Procedure:
Charge (2,6-difluoro-phenyl)-[4-(6-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (1.00 equiv, 1.44 moles, 520.00 g), methanol (197.66 moles, 8.00 L, 6.33 kg), and THF wetted 5% palladium on carbon (75.00 g) to a three gallon autoclave. Hydrogenate the reaction at 50 psi at room temperature while maintaining a temperature below 30° C. After 0.5 hours, cool to 26° C., and maintain for 2 hours. Filter and concentrate under reduced pressure. Filter to obtain solids, rinse with methanol then heptanes. An additional filtration yields a second batch of [4-(5-amino-6-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone. Dry under reduced pressure at 45° C. (445 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@@H]1CC[C@@H](c2ccccn2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 15.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.40 g, 5.05 mmol), (1R,3R)-3-(2-pyridyl)cyclopentylamine (985 mg, 6.07 mmol) and triethylamine (1.40 mL, 10.0 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1R,3R)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (325 mg, 15%) as a yellow powder.
Reaction SMILES: C(OC([NH:6][C:7]([NH:9][C:10]1[C:11]([C:16]([O:18]C)=O)=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:8])=O)C.C[O-].[Na+].CO>C(O)C>[OH:18][C:16]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:7]([SH:8])[N:6]=1
Reactant: CCOC(=O)NC(=S)Nc1cccnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1nc(S)nc2cccnc12
Yield: 100 %

Procedure:
A mixture of 37.2 g (0.13 mol) of N-ethoxycarbonyl-N'-(2-methoxycarbonyl-3-pyridinyl)thiourea and 33 mL of 25 percent sodium methoxide in methanol (0.14 mol) in 500 mL of absolute ethanol was heated to reflux with stirring. A solid began to form after about 5 min and after 1 hour heating was discontinued and the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water, acidified with acetic acid, and filtered to recover the solids. The solids were extracted on the filter with ether and then with acetone to obtain a fine powder that was difficult to filter. This was extracted with ether again (added while some acetone was still present) and, finally, with hexane to obtain the 23.3 g of title compound as a more easily filtered pale yellow granular solid melting above 300° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][N:18]=[C:17]([CH3:36])[CH:16]=2)=[CH:9][C:8]=1[Cl:37].O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:37][C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][N:18]=[C:17]([CH3:36])[CH:16]=2)[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cc(Cl)c(C(=O)NCC(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
To a solution of 38 mg (0.067 mmol) {2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-acetic acid methyl ester (Example 69) in 2 mL dioxane was added 2 mL water and 4 mg (0.083 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at room temperature for 4 hours and then poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 20 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield 10 mg (27%) of the desired compound as a light yellow solid. MS (ESI): m/z=555.119 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Yield: 99.2 %

Procedure:
A solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (5.8 g, 20 mmol) and 1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (7.4 mg, 10 μmol) in methanol (10 ml) was stirred at 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (5.8 g, 98% conversion, enantiomeric excess=97%, 95% pure by NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:26]=[N:25][C:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:31][CH:30]=2)=[CH:8][CH:9]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Solvent: CCO
Product: O=c1c2ccccc2nc(-c2ccc(N3CCCCC3)nc2)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
2-amino-N-(4-chlorophenyl)benzamide (0.318 g, 1.3 mmol) and 6-(piperidin-1-yl)nicotinaldehyde (1.3 mmol) were mixed in anhydrous EtOH (40 mL) and anhydrous CuCl2 (0.524 g, 3.9 mmol) was added. The reaction mixture was heated at reflux for 5 hours, cooled to room temperature, and stirred overnight. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 75% ethyl acetate/heptane, afforded the title compound as a white solid (35%). 1H-NMR (300 MHz, DMSO-6): δ 8.16 (d, J=8.0 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.86-7.91 (m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.54-7.59 (m, 1H), 7.36-7.50 (m, 5H), 6.64 (d, J=9.0 Hz, 1H), 3.49-3.53 (m, 4H), 1.48-1.58 (m, 6H). MS (APCI) m/z: 417 (M+H)+.
Reaction SMILES: O1C2C=CC=CC=2N=C1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Cl:28][Cl:29].[Cl:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>>[Cl:28][Cl:29].[Cl:30][C:31]1[O:32][C:33]2[CH:39]=[C:38]([Cl:28])[CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: Clc1nc2ccccc2o1
Agent: ClCl
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: O
Product: Clc1ccc2nc(Cl)oc2c1

Procedure:
Using the method of Example 1, 11.9 g (0.1 mol) of benzoxazole were reacted, with addition of 0.5 g of montmorillonite KSF, with chlorine gas at 100° C. After addition of 1.1 times the molar amount of chlorine gas, GC showed complete conversion into 2-chlorobenzoxazole. Further introduction of chlorine gas (an additional 1.0 times the molar amount) at 120-125° C. resulted in 80.6% conversion into 2,6-dichlorobenzoxazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:22][CH3:23]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:22][CH3:23])[NH:8][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10][C:11]2=[O:13]
Reactant: CCOC(=O)/C=C(\Nc1ccc(Br)c(OC)c1)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.8 %

Procedure:
To refluxing (˜300° C.) dowtherm A (100 ml) (mixture of biphenyl and diphenyl ether) was added ethyl (2Z)-3-[(4-bromo-3-methoxyphenyl)amino]-3-phenylacrylate (6.5 g, 17.27 mmol) in DOWTHERM A (5 mL, washed with 1 mL). Almost immediately, white solid begins to precipitate out of solution. Refluxing was continued for 40 min, and the reaction was cooled to RT and let stand for 1 h. The white solid was then filtered off, and the washed extensively with hexanes to give 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one as white crystals (4.72 g, 83%). 1H NMR (400 MHz, DMSO-d6): 11.69 (s, 1H), 8.19 (s, 1H), 7.82 (m, 2H), 7.59 (m, 3H), 7.35 (s, 1H), 6.33 (s, 1H), 3.96 (s, 3H). LRMS (CI, [M+H]) Calc'd=330.0. found=330.1.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[C:25]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[Cl:37])([CH3:28])([CH3:27])[CH3:26].FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[C:25]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=2)=[CH:31][C:30]=1[Cl:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=O)cc1Cl
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1Cl
Yield: 96 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-tert-butyl-3-chloro-benzaldehyde (68 mg, 0.35 mmol), 2-(3-trifluoromethyl-phenyl)-ethylamine (65 mg, 0.35 mmol) and sodium borohydride (20 mg, 0.52 mmol). The desired product (123 mg, 96%) was isolated without further purification as a colorless oil. MS (ISP) 370.1 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.Cl>C(O)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[CH:3]=[CH:4][NH:5][C:6](=[O:16])[CH2:7][C:8]=2[CH:9]=1
Reactant: COc1cccc(CC(=O)NCC(OC)OC)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NC=C2
Temperature: 0 °C
Yield: 51.6 %

Procedure:
A solution of N-(2,2-dimethoxy-ethyl)-2-(3-methoxy-phenyl)-acetamide (53.6 g, 0.21 mol) in acetic acid (140 mL) and aqueous 37% HCl (100 mL) was stirred at room temperature overnight. The reaction mixture was diluted with a ice/water mixture with vigorous stirring to yield a precipitate. The precipitate was filtered, rinsed with water, and then dissolved in dichloromethane, dried (MgSO4), concentrated and dried in high vacuum to give 8-methoxy-1,3-dihydrobenzo[d]azepin-2-one (20.5 g, 51%) as a tan solid. 1H-NMR (CDCl3) δ 8.23 (br s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.79, (s, 1H), 6.33 (d, J=9.1 Hz, 1H), 6.16 (dd, J=4.8, 9.3 Hz, 1H), 3.83 (s, 3H), 3.48 (s, 2H); LC/MS (ESI+): 190.05 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:25])([F:26])[F:24])[CH:9]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 92.4 %

Procedure:
Methyl acrylate (2.7 ml, 30 mmol), 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.48 g, 10 mmol), triethylamine (2.79 ml, 20 mmol), palladium acetate (45 mg, 0.2 mmol), tri-o-tolylphosphine (161 mg, 0.53 mmol) and acetonitrile (50 ml) were combined and the mixture heated at reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (3.2 g, 92%), m/z 347.0 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])[CH:18]=[N:19][CH:20]=1)=O)(C)(C)C>CCOCC.CO>[ClH:1].[NH:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C[C@@H]2C[C@H]2CO)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OC[C@@H]1C[C@H]1Cc1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2M anhydrous HCl in ether is added to a stirred solution of (1R,2S)-2-[[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]methyl]cyclopropylmethanol in dry MeOH at 0° C. The mixture is stirred at room temperature overnight and the conversion of starting material confirmed by TLC. The above solution is concentrated and purified by HPLC to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH2:13])=[S:11])=[CH:5][CH:4]=1.Cl.[C:15](=N)(N)[CH3:16].C([O-])(=O)C.[Na+].C(O)CCC>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15]([CH3:16])=[N:13][N:12]=[C:10]2[SH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=S)NN)cc1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-n2c(C)nnc2S)cc1
Yield: 83 %

Procedure:
A mixture of 13.5 parts of N-(4-methoxyphenyl)hydrazinecarbothioamide, 15 parts of ethanimidamide hydrochloride, 15 parts of sodium acetate and 120 parts of 1-butanol is stirred and refluxed for 1 hour. The reaction mixture is cooled, 100 parts of water are added, followed by the addition of 140 parts of petroleumether. The precipitated product is filtered off and dried, yielding 12.5 parts (83%) of 4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol; mp. 214.2° C.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([C:7](=[O:17])[CH:8]([Br:18])[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(CC(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2)cc1
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of the product of step 1 (60 g, 246 mmol) in CCl4 (900 mL) and CHCl3 (900 mL) was added dropwise a solution of Br2 (43.2 g, 270 mmol) in CCl4 (50 mL). After addition was completed, the mixture was concentrated to about 1/3 of its original volume. The mixture was washed with saturated NaHCO3 (500 mL) and Na2S2O8 (2×250 mL). The pale yellow solution was dried over Na2SO4 and concentrated to dryness. The residue was stirred in 10 % EtO2 /hexane for 20 h and filtered to give 59 g of the title compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=3[S:4](=[O:14])(=[O:13])[N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: O=S1(=O)N=C(NC2CCN(Cc3ccccc3)C2)Nc2ccc(Cl)cc21
Temperature: 110 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
A suspension of 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (100 mg; 0.4 mmol) 1-benzyl-3-aminopyrrolidine (0.35 ml; 2.0 mmol) was stirred at 110° C. for 72 h. The reaction mixture was concentrated in vacu and the residue was purified by flash chromatography using ethyl acetate/methanol 10:1 to give oily crystals (114 mg). These were recrystallised from ethyl acetate to give the title compound as white crystals (83 mg, 53%); m.p. 208.5-209.5° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[O:20][CH3:21])=[N:10][C:9]=1[CH3:22])(C)(C)C.Cl.O1CCOCC1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[O:20][CH3:21])=[N:10][C:9]=1[CH3:22]
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(NC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(Cl)ccc1-c1nc(C)c(N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
In methanol (25 ml), [2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamic acid tert-butyl ester (1.02 g, 2.87 mmol) prepared in the Step 28-1-1 was dissolved, and a 4-N hydrogen chloride-dioxane solution (25 ml) was added thereto. The mixture was stirred at a room temperature for 16 hours. Chloroform was added to the mixture, and the resulting mixture was neutralized with a saturated sodium bicarbonate solution. The resulting mixture was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (474 mg, 65%) as a light-brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:23]=[CH:22]3)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:37][CH2:38][CH2:39]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:8][C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:35])[CH2:39][CH2:38][CH2:37][N:11]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:23]=[CH:22]3)=[CH:16][CH:17]=1)=[O:7])[CH3:10]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Temperature: 55 °C

Procedure:
1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester is prepared by dissolving 2-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-ylamino}-malonic acid diethyl ester (9.25 mmol) in dimethylformamide (90 mL), followed by addition of 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol). The reaction mixture is stirred for approximately 24 hours to 48 hours. The mixture is filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained is chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40m column) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=1.CC(O)=O.OP(O)(O)=O>O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Br
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2oc3c(c2c1Br)NC(c1csc(C(C)C)n1)CC3=O
Temperature: 90 °C
Yield: 71.9 %

Procedure:
A mixture of 15A (2.8 g, 6.6 mmol), AcOH (10 mL) and H3PO4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15B (2 g, 71.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21]CC3C=CC=CC=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([OH:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(C)cc(OCc3ccccc3)c2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(O)c2)cc1C
Yield: 10.2 %

Procedure:
A mixture of 3-[4-(3-benzyloxy-5-methyl-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (3.56 g, 88.5 mmol) and 10% Pd/C (1.75 g) in ethyl acetate (90 mL) is purged with N2, then purged with H2 and stirred under a hydrogen balloon. Upon completion, the mixture is filtered through hyflo, and the solvent is removed in vacuo to afford 2.83 g (100%) the title compound. Rf=0.35 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C19H22O4 314, found 315 (M+1, 100%).
Reaction SMILES: C(N(CC)C([S:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]([C:16]1[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=1[CH2:25][O:26][CH3:27])=O)=S)C.C(O)=O.Cl.CO>C(Cl)Cl>[CH3:27][O:26][CH2:25][C:17]1[N:18]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[S:20][C:16]=1[C:14]1[S:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:13]=1
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(NC(C)=O)nc1COC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=CO
Product: COCc1nc(NC(C)=O)sc1-c1nc2ccncc2s1
Yield: 14.1 %

Procedure:
Crude 4-(2-acetamido-4-(methoxymethyl)thiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (4.485 g, 9.89 mmol) and formic acid (0.379 mL, 9.89 mmol) were added to a 150 mL round-bottomed flask, and the solution was stirred at reflux for approximately 24 hours until LCMS indicated that the reaction was complete. The formic acid was removed, and the reaction was quenched by addition of 1 N NaOH. No precipitate formed, and the solution was made neutral with HCl and extracted with EtOAc (5×75 mL) to provide crude product. The organic solution was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM, to provide N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.446 g, 1.39 mmol, 14.1% yield). LCMS (M+H) 321.1 calc. for C13H13N4O2S2 321.39, 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.61 (d, J=6.5 Hz, 1H), 8.18 (d, J=6.5 Hz, 1H), 4.82 (s, 2H), 3.51 (s, 3H), 2.27 (s, 3H).