Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=1
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)Cc1ccc(N)cc1
Yield: 879.1 %

Procedure:
To a solution of 4-nitrophenylacetamide 55 (3.2 g, 1.78 mmol) in methanol (50 mL) was added 10% Pd—C (0.32 g) and the resulted mixture was stirred at room temperature for 24 h under 1 atm hydrogen atmosphere. Pd—C was removed by filtration on Celite. The filtered solution was evaporated to provide 55a (2.35 g, 90% yield). 1HNMR (300 MHz, CDCl3-CD3OD): δ 7.06 (d, J=8 Hz, 2H), 6.72 (d, J=8 Hz, 2H), 3.41 (s, 2H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+].O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: BrCCCCCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: BrCCCCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Phenothiazine (5.0 g, 0.025 mol) and 1,6-dibromohexane (10.0 g, 0.065 mol) were dissolved in 100 mL of DMF (dimethyl formamide), and NaOH (sodium hydride, 0.98 g, 0.041 mol) was slowly added at room temperature. The resulting mixture was stirred at room temperature for 8 hr. After completion of the reaction, work-up was implemented in a solvent mixture of water and CHCl3 at 1:1. Thereafter, the organic layer was separated using an extraction method, and the solvent was removed under reduced pressure, followed by silica gel column chromatography (chloroform:hexane, 1:5), affording a transparent liquid product (4.5 g, 49.7%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([O:18][C:19]1[CH:41]=[CH:40][C:22]2[C:23]3[N:27]([CH2:28][CH2:29][O:30][C:21]=2[CH:20]=1)[CH:26]=[C:25]([C:31]1[N:32]([CH:37]([CH3:39])[CH3:38])[N:33]=[C:34]([CH3:36])[N:35]=1)[N:24]=3)([CH3:17])[C:12](OCC)=[O:13])C>C1COCC1>[CH:37]([N:32]1[C:31]([C:25]2[N:24]=[C:23]3[N:27]([CH2:28][CH2:29][O:30][C:21]4[CH:20]=[C:19]([O:18][C:11]([CH3:17])([CH2:12][OH:13])[CH2:10][OH:9])[CH:41]=[CH:40][C:22]=43)[CH:26]=2)=[N:35][C:34]([CH3:36])=[N:33]1)([CH3:39])[CH3:38]
Reactant: CCOC(=O)C(C)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CO)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To an ice-cooled suspension of LiAlH4 (34 mg, 0.892 mmol) in THF (3 mL) was added a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylmalonic acid diethyl ester (148 mg, 0.297 mmol) in THF (2 mL). The ice bath was removed and stirring at RT was continued for 1.5 h. To the reaction mixture was added EtOAc (5 mL) and stirring was continued for 10 min. An aqueous solution of Rochelle's salt was then added and stirring continued for a further 30 min. The mixture was filtered through a Celite® pad and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-12% MeOH in DCM) affording the title compound (79.4 mg, 65%). LCMS (Method B): RT 2.32 min [M+H]+ 414.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[C:25]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[C:25]([C:30]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:12])[F:14])[CH:6]=3)[C:31]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccccc1Cl)c1cccnc1C#Cc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cccc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
Add 1-azidomethyl-3-trifluoromethyl-benzene (152 mg, 0.75 mmol), (2-chloro-phenyl)-(2-pyridin-4-ylethynyl-pyridin-3-yl)-methanone (200 mg, 0.63 mmol), and toluene (2 mL) to a sealed tube. Flush with nitrogen, seal, and heat at 150° C. overnight. Concentrate to dryness and triturate with diethyl ether to afford the title compound (66 mg, 20%) as a pink solid: MS(IS) 520(M+1); TLC (5% MeOH/dichloromethane) Rf=0.48.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:20])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]nc1-c1cccc([N+](=O)[O-])c1
Product: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1

Procedure:
A 22.7 g. portion of 5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone in 230 ml. of phosphorus oxychloride is heated on a steam bath for 3 hours. The reaction mixture is poured portionwise into crushed ice with stirring. The resulting solid is collected by filtration, washed with water and then dried yielding 5-methyl-6-(m-nitrophenyl)-3-chloropyridazine, m.p. 169°-171° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)([Cl:17])=O>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([Cl:17])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1cc2ccccc2cc1O
Reaction time: 3 h
Yield: 585.5 %

Procedure:
494.0 g (2.63 mol) of 3-hydroxy-2-naphthoic acid and 2470.0 g=2872 ml of xylene are initially introduced into a 2 l four-necked flask having an internal thermometer, gas removal tube and stirrer, 6.0 g of N,N'-dimethylformamide are added, 328.0 g=201.1 ml (2.76 mol) of thionyl chloride are metered in at 47°-50°0C. over the course of 1 h and the mixture is subsequently stirred for 3 h until evolution of gas has ended. 3181.8 g of 3-hydroxy-2-naphthoyl chloride are obtained as a clear solution in xylene.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[CH2:9][C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11]>>[CH3:5][O:4][P:3]([CH2:9][C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])([O:6][CH3:7])=[O:2]
Reactant: C=CCOC(=O)CCl
Reactant: COP(OC)OC
Product: C=CCOC(=O)CP(=O)(OC)OC
Yield: 70.5 %

Procedure:
191 g of trimethylphosphite were added dropwise under stirring to 188 g of allyl chloroacetate (21/2 h) preliminarly heated to 118°. The reaction mixture was kept at this temperature for 4h, whereupon it was subjected to a distillation to give 205 g of allyl dimethylphosphono-acetate, b.p. 118°/0.1 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH3:14][NH:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[S:13])[N:15]([CH3:14])[NH2:16]
Reactant: O=[N+]([O-])c1ccc(N=C=S)c(Cl)c1
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 65 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of 60.0 g (0.280 mole) of 2-chloro-4-nitrophenyl isothiocyanate in 500 ml of ethanol was added 12.9 g (0.280 mole) of methylhydrazine. This mixture was heated and was stirred at 65° C. for approximately 18 hours. The mixture was then heated to reflux and was cooled. A solid had formed and was collected by filtration. The filter cake was rinsed with aqueous ethanol and was dried under reduced pressure to yield 59.0 g of 4-(2-chloro-4-nitrophenyl)-2-methyl-3-thiosemicarbazide, mp 164°-167° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[CH:13][CH:14]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:7]1[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)s2)c1
Temperature: 20 °C
Yield: 9 %

Procedure:
To a solution of 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (5.8 g, 123 mmol) in MeOH (50 mL) was added aqueous NaOH (4 N, 25 mL) and the mixture was refluxed for 2 h. After cooling to 20° C., solvent was removed. Water was added to dissolve the crude and then the solution was acidified with acetic acid. Solid was collected by filtration and washed with water and dried under high vacuum to give 1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxylic acid (5.1 g). MS(ES): 459 [M+H]+.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41](/[C:44](/[CH3:48])=[CH:45]/[CH2:46]O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](/[C:44](/[CH3:48])=[CH:45]/[CH2:46][O:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=3)=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Azodicarboxylic dipiperidide (0.731 g, 2.9 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.71 ml, 0.58 g, 2.9 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.483 g, 2.03 mmol) and (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol (0.500 g, 1.93 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 3 h. The resulting mixture was diluted with water and ethyl acetate (30 ml each), the aqueous layer collected and further extracted with ethyl acetate (30 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (20% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate as a gum; 0.69 g (75%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[CH3:9][C:6]1[C:7]([O:8][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: CCCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Product: CCCCC(CNc1nc(C)c(OC(=O)Oc2ccccc2)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of the method of Example 2, the title compound was prepared from 0.76 g (2.6 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylhexylaminopyrimidine and phenyl chloroformate (0.40 g, 2.6 mmol) to afford 0.74 g of product, mp: 76°-77° C. Mass spectrum m/e=419. NMR (CDCl3) delta: 7.4-6.9 (m, 10H); 4.99 (bs, 1H): 3.3 (q, 7, 4 Hz, 2H); 2.5 (t, 4 Hz, 2H); 2.3 (s, 6H): 1.8-1.1 (m, 8H). IR (CHCl3): 1780, 1583 cm-1. Anal. Calc'd for C25H29N3O3 : C, 71.57; H, 6.97: N, 10.02. Found: C, 71.51; H, 6.95; N, 10.09.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9]OCCCC)=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]=1[C@H:19]1[CH2:21][C@H:20]1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].[OH2:33]>O1CCOCC1.Cl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@H:19]2[CH2:21][C@H:20]2[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])[C:4]=1[O:15][CH2:16][O:17][CH3:18])(=[O:33])[CH3:9]
Reactant: O
Reactant: CCCCOC=Cc1ccc(F)c([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1OCOC
Agent: Cl
Solvent: C1COCCO1
Product: COCOc1c(C(C)=O)ccc(F)c1[C@H]1C[C@H]1NC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
(+,-)-N-(cis-2-(2-fluoro-5-butoxyvinyl-6-methoxymethoxy)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea (Example 55) was dissolved in dioxane and a few drops of dilute hydrochloric acid was added. The solution was stirred for 15 minutes, was diluted water and evaporated. The residue was co-evaporated with water to yield the title product as a solid. 1 H-NMR CDCl3 1.3 (q, 1H) 1.5 (q, 1H) 2.1 (q, 1H) 2.5 (s, 3H) 3.4 (m, 1H) 3.5 (s, 3H) 5.1 (m, 2H) 6.8 (m, 2H) 7.4-7.6 (m, 2H) 7.8 (d, 1H) 9.1 (bs, 1H) 9.8 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:13][C:14]([N:16]2[CH:21]=[CH:20][C:19](=[O:22])[CH2:18][C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:31](C)C=O.C(Cl)(=O)C(Cl)=O.N>ClCCl.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:13][C:14]([N:16]2[CH:21]=[CH:20][C:19](=[O:22])[CH2:18][C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:31])=[O:8]
Reactant: CN(C)C=O
Reactant: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(N)=O
Reaction time: 3 h

Procedure:
(S)-5-Bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid (72 mg) was dissolved in 2 ml dichloromethane and 0.001 ml dimethylformamide under argon. To this solution was added 0.02 ml oxalyl chloride and the solution was stirred for three hours. The solution was then slowly added at 0° C. to 0.5M NH3 in dioxane. After stirring for 10 minutes, the mixture was concentrated in vacuo and chromatographed (dichloromethane) to yield 26 mg (S)-5-bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzamide. MS (M+H) 463.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N[C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]([CH3:18])[CH3:17])[C:8]=1[C:9]#[N:10].[OH-].[Na+]>CCO>[CH:16]([NH:15][C:11]1[C:8]2[C:9]([NH2:10])=[N:5][S:1](=[O:3])(=[O:2])[NH:4][C:7]=2[CH:14]=[CH:13][CH:12]=1)([CH3:18])[CH3:17]
Reactant: CC(C)Nc1cccc(N)c1C#N
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Nc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Yield: 14.6 %

Procedure:
A solution of 2-amino-6-(isopropylamino)benzonitrile sulfamide (Example 90a) (0.14 g, 0.54 mmol) and NaOH (2 N, 0.54 mL) in EtOH (3 mL) was stirred at 90° C. under nitrogen for 0.5 hour. The reaction mixture was cooled to room temperature, and concentrated under vacuum. H2O (1 mL) was added and the reaction mixture was neutralized to pH˜3 with 10% AcOH. The resultant precipitate was extracted with EtOAc, and after evaporation of solvents the residue was purified by preparative thin layer chromatography using a DCM/EtOAc (4:1) solution as eluant, to give N5-isopropyl-1H-benzo[c][1,2,6]thiadiazine-4,5-diamine-2,2-dioxide (0.02 g). 1H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J=6.4 Hz, 6H), 1.84 (bs, 1H), 5.24 (bs, NH), 6.22-6.19 (m, 2H, NH), 7.09 (t, J=8.0 Hz, 1H), 7.48 (bs, 2H). MS 255 (MH+).
Reaction SMILES: Br[CH:2]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[CH3:17][SH:18].[OH-].[Na+]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][CH2:6][CH:2]([S:18][CH3:17])[C:3]([OH:5])=[O:4])=[CH:10][CH:11]=1
Reactant: CS
Reactant: COc1ccc(CSCC(Br)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSCC(SC)C(=O)O)cc1

Procedure:
A solution of 2-bromo-3-(4-methoxybenzylmercapto) propanoic acid (15 g.), methylmercaptan (3 g.) and sodium hydroxide (4.6 g.) in 95% ethanol (25 ml.) is refluxed for twelve hours. The sodium bromide is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(4-methoxybenzylmercapto)-2-(methylthio)propanoic acid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: OC(=S)CCCc1nnnn1C1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Cyclohexyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)thiobutyramide (yield: 47%), colorless liquid, nD18 =1.5290.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]2)=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([N:34]3[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: O=C1CN(c2ncc(Br)s2)CCCN1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
N-[3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (Intermediate IV, 35.4 g, 93 mmol) and 4-(5-bromo-1,3-thiazol-2-yl)-1,4-diazepan-2-one (21.5, 78 mmol) were combined in a 2 L RB flask follwed by DMF (473 mL) and aqueous Na2CO3 solution (1 M, 311 mL). The solution was sparged with N2 for 15 minutes and then [Pd(Ph3P)4](3.6 g, 3.11 mmol) was added. The mixture was heated at 85° C. for 12-15 hours. The reaction was cooled to 0° C. and saturated NH4Cl (500 mL) was added followed by EtOAc (2 L) and DCM (2 L). The aqueous layer was extracted with DCM (1 L) and the combined organic layer was washed with 10% aqueous LiCl solution (1 L) and then dried over Na2SO4. The organic layer was concentrated and slurried in MTBE (500 mL) and filtered. The solid was then dissolved in THF (870 mL), degassed and then treated with 300 wt % Silicycle Si-triamine resin at 40° C. for 1 hour. The suspension was then filtered, the residue washed with 40° C. THF (400 mL) and concentrated. A final slurrying in MTBE (200 mL) for 1.5 hours, filtration and drying gave 13.1 g of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (37%). MS APCI: [M+H]+ m/z 449.2. 1H NMR (600 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.79 (d, J=6.0 Hz, 1H); 7.77 (s, 1H), 7.57 (t, J=4.7 Hz, 1H); 7.44 (s, 1H); 7.34 (s, 1H); 7.23 (d, J=4.9 Hz, 1H); 6.9 (s, 1H), 4.19 (s, 2H); 3.76 (m, 2H); 3.19 (m, 2H); 2.26 (s, 3H), 1.76 (m, 2H). rhSyk=+++
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:19]=[C:18]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Oc1cccc2ccccc12
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Yield: 80.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (25.2 mL, 10.1 mmol), ethyl 6-chloro-4-(naphthalen-1-yloxy)nicotinate (3.63 g, 11.1 mmol), potassium phosphate (2.35 g, 11.1 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.231 g, 0.252 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.160 g, 0.277 mmol) were reacted in toluene (25 mL) and water (8 mL) to afford ethyl 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinate (3.30 g, 80.0% yield) as yellow solid. 1H NMR (CDCl3) δ 9.90 (bs, 1H), 8.91 (s, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.77 (d, 1H), 7.53 (m, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 7.14 (d, 1H), 6.18 (s, 1H), 5.90 (s, 1H), 4.37 (quart, 2H), 1.76 (s, 3H), 1.33 (t, 3H); Mass spectrum (apci) m/z=406 (100) (M+H).