Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Mg]Br>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: Br[Mg]c1ccccn1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.03 h

Procedure:
LaCl3-2LiCl (0.6 M in THF, 0.78 mL, 0.47 mmol) was added dropwise by syringe to a solution of (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (101.4 mg, 0.226 mmol, Intermediate 41: step d) in dry THF (2 mL). After 2 minutes, the solution was cooled in an ice bath and pyridin-2-ylmagnesium bromide (2.8 mL, 0.7 mmol) was added dropwise via syringe. The reaction was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride and removed from the cold bath. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.65-8.61 (m, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.84-7.79 (m, 3H), 7.73-7.67 (m, 2H), 7.51 (s, 1H), 7.49-7.44 (m, 2H), 7.34-7.29 (m, 1H), 7.24-7.19 (m, 1H), 6.34 (s, 1H), 4.36 (s, 2H), 4.07 (s, 3H), 3.43 (s, 3H), 3.01 (s, 3H); MS m/e 549.2 [M+H]+.
Reaction SMILES: C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C(O)=O)(NC3=O)C4)C2)C2C(=C3CCOC3=CC=2)N=1)C.[CH2:42]([O:44][C:45]1[CH:54]=[C:53]([O:55][CH:56]2[CH2:73][CH:72]3[CH:58]([C:59](=[O:85])[N:60]([CH3:84])[CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=[CH:66][CH:67]4[C:69]([C:75]([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=[O:76])([NH:70][C:71]3=[O:74])[CH2:68]4)[CH2:57]2)[C:52]2[C:47](=[C:48]([CH3:88])[C:49]([O:86][CH3:87])=[CH:50][CH:51]=2)[N:46]=1)[CH3:43]>>[CH2:42]([O:44][C:45]1[CH:54]=[C:53]([O:55][CH:56]2[CH2:73][CH:72]3[CH:58]([C:59](=[O:85])[N:60]([CH3:84])[CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=[CH:66][CH:67]4[C:69]([C:75]([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:79])=[O:80])=[O:76])([NH:70][C:71]3=[O:74])[CH2:68]4)[CH2:57]2)[C:52]2[C:47](=[C:48]3[CH2:88][CH2:87][O:86][C:49]3=[CH:50][CH:51]=2)[N:46]=1)[CH3:43]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)CCO3
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)CCO3

Procedure:
The title compound (9) was prepared from 17-[2-ethoxy-8,9-dihydrofuro[2,3-h]-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (8) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=667 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([C:8]1[C:9]2[CH2:30][NH:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
tert-Butyl 4-benzyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (270 mg, 0.54 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (0.017 mL, 0.54 mmol) was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure yielding 4-benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (150 mg, 69.6%) which was used in the subsequent step as such.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]([O:23]C)=[O:22])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[OH-].[Na+].O>O1CCCC1>[S:1]1[C:5]([C:6]2[C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]([OH:23])=[O:22])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.36 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (43.2 mg, 1.08 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 2-(benzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (80 mg, 59%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:16][CH3:17]>Cl.CO>[CH3:17][O:16][C:3]1[C:2]2[O:1][C:13]([CH3:15])([CH3:14])[CH2:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: C=C(C)Cc1cc(C(=O)OC)cc(OC)c1O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2c(c(OC)c1)OC(C)(C)C2
Yield: 53.7 %

Procedure:
A solution of methyl 4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate (150 g, 0.63 mol) in conc. HCl (300 mL) and MeOH (300 mL) was heated to reflux for 2 h. TLC (EtOAc/petroleum ether=1/5) showed the reaction was complete. The solution was evaporated, and the residue was extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by column chromatography (EtOAc/petroleum ether=1/30) to give the title compound (80 g, 53%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.46 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.05 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CSc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To 4-(methylthio)aniline (1 mL, 8.19 mmol) in dichloromethane (20 mL) was added pyridine (2 mL, 24.6 mmol). The resulting solution was cooled to 10-15° C. and 4-chlorobenzoyl chloride (1.14 mL, 9.00 mmol) was added over 5 min. The mixture was stirred at room temperature for 90 min. The precipitate was filtered off, washed with dichloromethane, 1M aqueous sodium hydroxide solution and 1M aqueous hydrochloric acid solution to afford 2.12 g (93%) of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([CH3:35])[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([NH:19][C:20]([C:22]3[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][CH:23]=3)=[O:21])[S:17][CH:18]=2)=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[NH2:27][C:25]1[S:26][C:22]([C:20]([NH:19][C:16]2[S:17][CH:18]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:35])=[CH:9][CH:10]=3)[N:15]=2)=[O:21])=[CH:23][N:24]=1
Reactant: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)OC(C)(C)C)s3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(N)s3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
TFA (0.100 mL) was added to a solution of tert-butyl 5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-ylcarbamate (80 mg, 0.19 mmol) in CHCl3 (1 mL). The resulting solution was stirred at RT overnight. Then the solvents were evaporated and the crude product was dissolved in H2O. After neutralization with NaHCO3 saturated aqueous solution, it was extracted with AcOEt, dried and concentrated. Purification by column chromatography (100% AcOEt) yielded 2-amino-N-(4-p-tolylthiazol-2-yl)thiazole-5-carboxamide (40 mg, 67%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]=[C:16]1[O:17][C:13]([C:4]2[S:3][C:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:6][C:5]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:14][NH:15]1
Reactant: Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1

Procedure:
Prepared from 5-(2-amino-4-phenyl-thiazol-5-yl)-3H-[1,3,4]oxadiazol-2-one and phenyl-acetyl chloride.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:14]([O:16][C:17](=[O:35])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[C:26]3[O:31][C:32](Cl)=[CH:33][C:25]=23)[CH:21]=[N:20]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:35])[CH:23]=2)=[C:25]2[CH:33]=[C:32]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:26]=12
Reactant: OB(O)c1cccc2cnccc12
Reactant: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(-c4cccc5cnccc45)cc23)cn1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A solution of isoquinoline-5-boronic acid (53.9 mg, 0.312 mmol) and ethyl[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]acetate (50.0 mg, 0.156 mol) in 1,4-dioxane (0.85 mL) and H2O (0.3 mL) was charged with potassium carbonate (32 mg, 0.23 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (1 mg, 0.002 mmol) under an atmosphere of nitrogen. The mixture was heated in a microwave reactor at 100° C. for 40 min. Purification of the residue by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 27 mg (41%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 9.36 (s, 1H), 8.57-8.63 (m, 1H), 8.52 (d, J=6.06 Hz, 1H), 8.37 (d, J=7.33 Hz, 1H), 8.27 (d, J=8.08 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J=7.58 Hz, 2H), 7.85 (t, J=7.83 Hz, 1H), 7.55-7.62 (m, 1H), 7.53 (s, 1H), 4.28 (q, J=7.16 Hz, 2 H), 1.95 (s, 2H), 1.32 (t, 3H); MS (ESI): 415.16 [M+H]+; HPLC tR=0.94 min (TOF: polar—3 min).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCCCc1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=374.4 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (5-bromo-pentyl)-benzene. (5-Bromo-pentyl)-benzene is a known compound and has been prepared as described in the following reference: J. Thomas; W. Marlow; J. Med. Chem.; 6; 1963; 107-111.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:4]=13.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[N+:17]([C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C:4]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:3]2=3)[CH:8]=1)([O-:19])=[O:18]
Reactant: c1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCC1

Procedure:
Following the procedure of Example 1, step 2, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole (7.5 g, 35 mmol) and potassium nitrate (3.6 g, 35 mmol) in concentrated sulfuric acid (100 mL) provided 2-nitro-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=O)[C:8]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[N:21][C:20]3[CH:22]=[CH:23][C:17]([I:16])=[CH:18][CH:19]=3)[C:8]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Reactant: Nc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1c(C=Nc2ccc(I)cc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
An amount of 20.6 mmol of 3-phenyl salicylaldehyde (2) (4.08 g) was dissolved in 150 ml of toluene. After addition of 4-iodoaniline (5.42 g/24.8 mmol) and a few crystals of para-toluenesulfonic acid, the reaction mixture was stirred under reflux for three hours applying a Dean-Stark-trap. After cooling down to room temperature, sodium hydrogencarbonate solution (150 ml) was added. The organic phase was separated and filtered over sodium sulfate and silica. Removing the solvent and recrystallization from ethanol at −20° C. gave the title compound as a red solid. Yield: 7.25 g (88%).
Reaction SMILES: NC1C=C(F)C(F)=CC=1S(N)(=O)=O.C(N=C=S)C.[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=S)(=[O:30])=[O:29]>>[CH2:35]([NH:34][C:32]1[NH:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[S:28](=[O:30])(=[O:29])[N:31]=1)[CH3:36]
Reactant: CCNC(=S)NS(=O)(=O)c1cc(F)c(F)cc1N
Agent: Nc1cc(F)c(F)cc1S(N)(=O)=O
Solvent: CCN=C=S
Product: CCNC1=NS(=O)(=O)c2cc(F)c(F)cc2N1

Procedure:
Starting from 2-amino-4,5-difluorobenzenesulfonamide and ethyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4,5-difluorobenzenesulfonyl)-N′-ethylthiourea was prepared. The crude compound was used without further purification in a cyclisation step analogous to the one described in Example 4b to give the title compound; m.p. 246-252° C.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.ClCCl>>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 64, 175 mg) in dry dichloromethane (DCM) (6 mL) TFA (2 mL, 26.0 mmol) was slowly added and the reaction mixture was stirred for 1 h at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a colourless solid (122 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][OH:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH:13]=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CC2CO)cc1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Product: COc1ccc(C2CC2C=O)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-methanol (0.30 g, 1.52 mmol) obtained in Step A was dissolved in DMSO (5 mL), 2-iodoxybenzoic acid (1.248 g, 4.58 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/3) to obtain the title compound (0.265 g, 89%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:32]=[CH:31][CH:30]=[CH:29][C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:26](=[O:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[O:10])=[O:7]>O.[OH-].[Na+].C(O)C>[Cl:3][C:4]1[CH:32]=[CH:31][CH:30]=[CH:29][C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]([OH:28])[CH3:27])=[CH:16][CH:17]=1)=[O:10])=[O:7]
Reactant: CC(=O)C(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)C(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 0.1 g of sodiumborohydride in a mixture of 0.5 ml of water and 0.1 ml of 2 N sodium hydroxide solution was added to a suspension of 1.55 g of N-(2-chlorobenzoyl)-N'-[4-(α-acetylbenzyloxy)phenyl]urea obtained according to the method described in example 1, in 20 ml of ethanol. After stirring for another hour at room temperature the precipitate was sucked off, washed with ethanol and dried; 0.91 g of the desired product was obtained with a melting range of 142°-144° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH3:31])=[N:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH2:30]([NH:29][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:12]=2)[NH:8][N:9]=1)[CH3:31]
Reactant: CCNc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12

Procedure:
8.2 g (19.59 mmol) 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-3-(ethylamino)-1H-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 19, was stirred in 147 mL of a 4 M solution of HCl in dioxane, at 55° C. (bath temperature) for 2 hours. On cooling, the volatiles were removed under vacuum to furnish 4-[3-(ethylamino)-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile, hydrochloride salt (Cpd. No. 161, Table 2). The hydrochloride salt was converted to the free base as follows: the hydrochloride salt was suspended in a mixture of EtOAc and 2 M aqueous sodium hydroxide and heated on a steam bath until the solid completely dissolved. On cooling, the mixture was extracted and the organic phase was washed successively with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The resulting crude product was purified by extracting twice with hot EtOAc (each time stirred in hot EtOAc, allowed to cool and filtered). The product was dried under vacuum to afford 4-[3-(ethylamino)-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (4.6 g, 73.7%) (Cpd. No. 121, Table 2). 1H-NMR (DMSO-D6, 400 MHz): δ=11.38 (br s, 1H), 9.44 (br s, 1H), 7.51 (m, 1H), 7.20 (d, 1H), 7.12 (dd, 1H), 5.91 (t, 1H), 4.34 (s, 1H), 3.21-3.27 (m, 2H), 2.01 (s, 6H), 1.19 (t, 3H) ppm. m.p.=247.6° C.
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][OH:3].C=C.[K+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)([O-:11])=[O:10].O>C(O)CO>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:3][CH2:2][CH2:1][OH:5])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])CO
Agent: C=C
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
200 ml of ethylene glycol and 40 ml of the mono-potassium ethylene glycolate solution prepared under Example 3 were introduced initially under nitrogen and were heated to 65° C. in a 2 l reaction vessel fitted with a stirrer. Over the course of 5 h, 162 g of molten 2,4-dinitro-chloro-benzene and the remainder of the mono-potassium ethylene glycolate solution in ethylene glycol were simultaneously metered in. The mixture was then stirred for one hour at 65° C., and then 600 ml of water were added. The precipitate which formed was filtered off and washed with 1000 ml of water and dried, giving 169.7 g of 2-(2′,4′-dinitrophenoxy)-ethanol in a purity of 92%. Hence, a yield of 92% is achieved based on 2,4-dinitrochlorobenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of 2,5-Dibromo-pyridine (6 g, 25.327 mmol) in DMF (60 mL) is added sodium thiomethoxide (1.95 g, 27.86 mmol) at 0° C. Reaction mixture is allowed to come to room temperature and resulting reaction mixture is stirred at room temperature for 12 h. Reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by column chromatography using silica (100-200) mesh size and using 4% ethyl acetate in hexane as an eluent to get (4.5 g) of yellow solid title compound. 1H-NMR (400 MHz, DMSO) δ: 2.49 (s, 3H), 7.29 (d, 1H, J=8.76 Hz), 7.85-7.88 (dd, 1H, J1=2.44 Hz, J2=8.48 Hz), 8.55 (d, 1H, J=2.4 Hz). LC-MS (m/z): M+H=206.1.