Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3]NC(NC1C2C(=C(F)C=CC=2)CC1)=O.[CH:18]1([C:27]([NH2:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH:27]2[NH:29][CH2:3][CH2:2][O:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: O=C(NCCCl)NC1CCc2c(F)cccc21
Reactant: NC(=O)C1CCc2ccccc21
Product: c1ccc2c(c1)CCC2C1NCCO1

Procedure:
As depicted in Scheme 2, the reaction of an appropriately substituted indanyl amine, for example 4-fluoroindanylamine (known compound, U.S. Pat. No. 5,486,541) with 2-chloroethyl isocyanate (SM4) under basic conditions, in an appropriate solvent yielded the corresponding indanyl carboxamide intermediate (a), for example, [(2-chloroethyl)amino]-N-(4-fluoroindanyl)carboxamide. Intermediate (a) was heated under basic conditions in an appropriate solvent to yield the appropriate indanyl 1,3-oxazolidine, a compound of formula I and an intermediate (b), for example, 2-[aza(4-fluoroindanyl)methylene]-1,3-oxazolidine, described in detail in Example 2, Step B, as set forth below. Compound (b) was reacted with an isothiocyanate, for example, methyl isothiocyanate, under basic conditions yielding the corresponding amino methane-1-thione, for example, 2-[aza(4-fluoroindanyl)methylene](1,3-oxazolidin-3-yl)(methylamino)methane-1-thione, a compound of formula I, described in detail in Example 2, Step C, as set forth below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-phenylamine to give N1-(4-chloro-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 381(MH+).
Reaction SMILES: B1C2CCCC1CCC2.[F:10][C:11]([F:28])([F:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=2)[CH:13]=1.[OH-:29].[Na+].OO>C1COCC1>[F:10][C:11]([F:27])([F:28])[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:29])=[CH:21][CH:20]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
9-BBN (277 mL, 139 mmol) was added to a solution of 1-(trifluoromethyl)-3-(4-vinylphenoxy)benzene (24.4 g, 92 mmol) in THF (200 mL) at 0° C., and the resulting reaction mixture was stirred at room temperature overnight. To the mixture was added 3M NaOH solution (140 mL) and 30% hydrogen peroxide (123 mL) slowly at 0° C., and the reaction mixture was stirred at 50° C. for 2 h. Purification via column chromatography then afforded the title compound as a colorless oil (17 g, 63.8% yield). LCMS: rt=1.79 min, [M−OH]+=265
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([CH3:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)c(C)cc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
To a suspension of 0.125 g (0.57 mmol) 5-hydroxy-6-methyl-1H-indole-2-carboxylic acid ethyl ester in 3 mL tetrahydrofuran, 98 mg (0.68 mmol) 1-isopropyl-piperidin-4-ol and 0.18 g (0.68 mmol) triphenylphosphine were added. The reaction was cooled to 0° C., 0.16 g (0.68 mmol) di-tert-butyl azodicarboxylate were added and the cooling bath was removed. After stirring 18 h at room temperature the volatile components were evaporated and the residue was purified by flash chromatography on silica gel using a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant, to afford 74 mg (38%) of the title compound as a light-yellow foam.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][N:9]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:39][CH2:40][CH3:41])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: CC(C)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN([C@@H]1C[C@@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
N-[(3R,5S)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.047 g, 0.088 mmoles, Example 27a), 1-iodopropane (0.052 mL, 0.53 mmoles), cesium carbonate (0.043 g, 0.13 mmoles) and anhydrous N,N-dimethylformamide (0.50 mL) was stirred at 55° C. (oil temperature) over night, concentrated by rotary evaporation, taken up diethylether and washed with water once. The aqueous phase was washed with a second portion of diethylether, the combined organic phases were washed with brine, dried with potassium carbonate, filtered and concentrated by rotary evaporation. Flash chromatography of the crude product on silica using dichloromethane-methanol (99:1) as eluent gave the title compound as a colourless oil. LC-MS (APCI) m/z 575 (M+1). 1H NMR (CDCl3) δ 8.12 (d, J=8 Hz, 2H), 7.74–7.69 (m, 5H), 7.72 (d, J=8 Hz, 2H), 7.44–7.34 (m, 4H), 5.01 (s, 2H), 4.48 (dd, J1=8 Hz, J2=10 Hz, 1H), 3.45 (dt, J1=3 Hz, J2=9 Hz, 1H), 3.10–2.98 (m, 2H), 2.24 (ddd, J1=2 Hz, J2=10 Hz, J3=14 Hz, 1H), 2.20–2.10 (m, 1H), 2.03 (dt, J1=9 Hz, J2=14 Hz, 1H), 1.73–1.51 (m, 2H), 0.87 (d, J=7 Hz, 3H), 0.84 (d, J=7 Hz, 3H) and 0.82 (obscured t, J=7 Hz, 3H) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([CH:15]([N:20]=[C:21]=[S:22])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])=[S:22])(=[O:10])=[O:11]
Reactant: CCCCC(CC)N=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CCCCC(CC)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Yield: 36 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1-ethylpentyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 36%), 1H-NMR (DMSO-d6): δ0.8 (2 q, 6H, 2×CH3), 1.2 (m, 4H), 1.5 (m, 4H), 4.20 (sextet, 1H, CH), 6.55 (br, 2H, NH2), 6.65 (s, 1H, H4), 7.85 (br d, 1H, NH), 11.3 (br s, 1H, NH).
Reaction SMILES: [ClH:1].[O:2]=[C:3]([CH2:5][N:6]([C:8](=[NH:10])[NH2:9])[CH3:7])O.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)Cl>[ClH:12].[CH3:7][N:6]([CH2:5][C:3]([Cl:1])=[O:2])[C:8]([NH2:9])=[NH:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CN(CC(=O)O)C(=N)N
Agent: Cl
Solvent: ClCCl
Product: CN(CC(=O)Cl)C(=N)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Creatine hydrochloride (1.85 g., 0.01 mole) in methylene chloride (50 ml.) was treated with phosphorous pentachloride (2.06 g., 0.01 mole) at room temperature. The mixture was stirred overnight at room temperature and the acid chloride product filtered off, washed with methylene chloride and dried.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH:1]1[C:11]2[CH2:10][N:9]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:21]4[CH:20]=[CH:19][O:18][C:17]=4[CH3:16])=[O:23])=[N:30][CH:29]=3)=[O:32])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: Cc1occc1C(=O)Nc1ccc(C(=O)Cl)cn1
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Nc3ccccc32)cn1

Procedure:
As described for Example 20, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine is reacted with 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](O)=[O:27])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1[CH:39]=[N:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[N:38]1[CH:39]=[CH:34][CH:35]=[C:36]([CH2:40][NH:41][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:32])([F:33])[F:1])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)[CH:24]=2)[CH:37]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Reactant: NCc1cccnc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)NCc5cccnc5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid and picolamine (Aldrich Cat. No. A65409). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[N:11]=[CH:10][N:9]=[CH:8]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][CH:2]2[O:1][C:6]3=[C:7]4[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3]2)[N:11]=[CH:10][N:9]=[CH:8]4)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncncc4c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6ncncc6c5O4)CC3)c2c1

Procedure:
(2R)-2,3-Dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethyl-4-methylbenzenesulfonate (800 mg, 3.7 mmole) was dissolved in a mixture of DMF/THF 1:1 v/v (30 mL) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (800 mg, 4 mmole) added, followed by the addition of sodium bicarbonate (1.0 gm, 9.4 mmole) and the mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between methylene chloride and water. The organic phase was separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a foam. Treatment of this foam with 3% methanol in chloroform yielded 320 mg (35%) of the (S)-enantiomer of the title compound as a yellow crystalline hemihydrate, m.p. 233-235° C.
Reaction SMILES: C([O:4][CH:5]([C:7]1[N:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[Cl:14])[CH3:6])(=O)C.[OH-].[Na+]>O1CCCC1>[Cl:13][C:9]1[C:8]([Cl:14])=[C:7]([CH:5]([OH:4])[CH3:6])[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)OC(C)c1ncnc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)c1ncnc(Cl)c1Cl

Procedure:
In 50 ml of tetrahydrofuran was dissolved 4.0 g of 6-(1-acetoxyethyl)-4,5-dichloropyrimidine, and to the mixture was slowly added dropwise 30 ml of an 1N-sodium hydroxide aqueous solution under stirring. After the dropwise addition, the mixture was further stirred for 1 hour at room temperature to complete the reaction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:2]1
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1cccc(F)c1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1cccc(F)c1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 59.7 %

Procedure:
Using Method H, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (120 mg, 0.39 mmol) and 2-fluoro-6-methoxyphenylboronic acid (250 mg, 1.47 mmol) were reacted (refluxed 2 hours). After purification the title compound (82 mg, 60% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 7.93 (m, 1H), 7.75 (m, 1H), 7.36 (apparent q, J=7.0 Hz, 1H), 6.84 (m, 2H), 3.69 (s, 3H), 2.96 (m, 1H), 0.85 (m, 2H), 0.63 (m, 2H). MS APCI, m/z=353 (M+H) HPLC 1.74 min.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][CH:5]([NH2:7])[CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:6][CH:5]([NH:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(N)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1CC(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a stirred solution of 3-methylcyclobutanamine hydrochloride (0.100 g, 0.8 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.125 g, 93%). The material was used without further purification.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](=[O:26])[CH:14]=2)[C@H:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9]1)C1C=CC=CC=1.CC(O)=O>CCO.[Pd]>[C:27]1([C@H:10]2[C@@H:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](=[O:26])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cn1c(C)cc([C@H]2CN(Cc3ccccc3)C[C@H]2c2ccccc2)cc1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C)cc([C@H]2CNC[C@H]2c2ccccc2)cc1=O
Reaction time: 24 h

Procedure:
A mixture of 4-(1-benzyl-cis-3-phenylpyrrolidin-4-yl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 5 above (0.30 g, 0.66 mmol), 10% Pd on carbon (100 mg), and HOAc (1 mL) in EtOH (10 mL) was stirred under an atmosphere of hydrogen at ambient pressure and temperature for 24 h. The catalyst was removed by filtration and the filtrate solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and the solvent was removed in vacuo to give the title compound as an oil (0.2 g, HPLC RT=4.98 min, method A).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:1]
Reactant: O=S(=O)(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
N-[3-(Hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl]benzenesulfonamide (379 mg) and triethylamine (1 mL) were dissolved in dimethyl sulfoxide (5 mL), and sulfur trioxide•pyridine complex (549 mg) was added at room temperature. After stirring at room temperature for 18 hr, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:3) to give the title compound as a pale-yellow oil (yield 331 mg, yield 88%).
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(COc2ccc(Br)cn2)cc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a diethyl ether (150 mL) solution of 5-bromo-2-(4-fluoro-benzyloxy)-pyridine (3.75 g 13.3 mmol) described in Manufacturing Example 58-1-1 was added n-butyl lithium (2.55 M n-hexane solution, 6.26 mL, 16.0 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (1.54 mL, 20.0 mmol) was then added dropwise and stirred for 5 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.23 g, 72.5%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[C:27]([C:23]1[CH:22]=[C:21]([S:20][C:12]2[N:11]=[C:10]([NH:9][C:6]3[NH:7][N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: COC(=O)c1cccc(Sc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Sc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine (110 mg, 0.26 mmol) in a mixture of THF/water (1/1, 10 mL) is treated with 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hours at room temperature and then neutralized with 1M HCl (0.75 mL, 0.75 mmol). A solid forms and is collected by filtration to afford the desired [2-(3-carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(O)C.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CNCCN1
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(CN2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise to a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the reaction temperature at 20° C. during the addition. The reaction mixture was stirred for an additional 11/2 hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CH2Cl2 /methanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (56% of theory).