Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CC(C)([O-])C.[K+].[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]3[CH2:26][O:25]3)[CH:22]=[CH:23][C:16]1=2.Cl>C(OCC)(=O)C.CS(C)=O>[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]([OH:25])[CH2:26][O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:22]=[CH:23][C:16]1=2
Reactant: c1cc2cc(C3CO3)ccc2o1
Reactant: OCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC(COCc1cccnc1)c1ccc2occc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoxide was heated to 80° C. Thereto was added 2.4 g of 2-(benzo[b]furan-5-yl)oxirane. The resulting mixture was stirred at 85°-90° C. for 15 minutes. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 9.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=50/1) to obtain 0.56 g of 1-(benzo[b]furan-5-yl)-2-(pyridin- 3-ylmethoxy)ethanol (compound No. 339).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine (10 g) was dissolved in dichloromethane (200 ml) and triethylamine (20.6 g) was added. The mixture was stirred at room temperature and piperazine-1-carboxylic acid tert-butyl ester (9.54 g) was added in portions. The mixture was stirred at room temperature overnight. Mixture was washed with water (200 ml) then brine (100 ml). The organic layer was dried (MgSO4) then evaporated under reduced pressure to afford 4-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (17.9 g) as a white solid. 1H NMR (CDCl3): δ 6.11 (s, 1H), 3.58 (m, 4H), 3.44 (m, 4H), 2.42 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:42]([O:46][C:47](=[O:58])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)[NH2:49])([CH3:45])([CH3:44])[CH3:43]>C(#N)C>[CH2:4]([O:3][C:1]([NH:11][C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:17]([NH:49][C@@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)[C:47]([O:46][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:58])=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of N-carbobenzyloxy-L-leucine (8.6 g) in acetonitrile (150 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.83 g) and 1-hydroxybenzotriazole (4.81 g). After stirring for 30 mins at 20° C. L-tyrosine tert-butyl ester (7.7 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (300 ml) and ethyl acetate (150 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (150 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (150 ml), water (2×150 ml) and brine (100 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (15 g, 96%). LCMS: Rt 3.56 min; m/z 485 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH2:30]1[NH:35][CH2:34][CH2:33][N:32]2[CH:36]=[CH:37][CH:38]=[C:31]12.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[N:35]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=2)=[O:27])[CH2:34][CH2:33][N:32]2[CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: c1cc2n(c1)CCNC2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCn5cccc5C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83 mg (0.21 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 37 mg (0.24 mmol) 1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine in 0.10 mL (0.72 mmol) TEA and 2.0 mL DMF were mixed with 77 mg (0.24 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the residue was dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH:29][CH2:30][CH2:31][OH:32]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N:29]([CH2:30][CH2:31][OH:32])[CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: OCCNCc1cccs1
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(N(CCO)Cc2cccs2)cc(C)nc1Oc1c(C)cc(C)cc1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in 1-methyl-2-pyrrolidinone was heated at 130° C. overnight. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR (CDCl3) d 7.22(m,1H), 6.94m,2H), 6.84(s,2H), 6.44(s,1H), 4.52(s,2H), 3.91(s,3H), 3.679t,2H), 3.369t,2H), 2.279s,3H), 2.20(s,3H), 2.07(s,6H) ppm.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][NH:6][C:7](=[O:10])[NH:8][NH2:9].[CH:12]([O-])([O-])OCC>>[CH3:2][CH:3]([CH3:11])[CH2:4][CH2:5][N:6]1[CH:12]=[N:9][NH:8][C:7]1=[O:10]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)CCNC(=O)NN
Agent: Cl
Product: CC(C)CCn1cn[nH]c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 13.0 g of 4-(3-methylbutyl)semicarbazidehydrochloride (71.6 mmol) and 60 ml of ethyl orthoformate was stirred at 110° C. for two hours. After cooling, the mixture was subjected to column chromatography using silica-gel (eluate; ethyl acetate:hexane=1:2 to 2:1 to ethyl acetate to ethyl acetate:methanol=10:1). The desired fraction was concentrated. The crystals thus given was recrystallized from ethyl acetate-petroleum ether to give 7.0g of 4-(3-methylbutyl)-3(2H,4H)-1,2,4-triazolone (63%) as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].O.[C:15]([OH:19])(=[O:18])[CH:16]=O.P(=O)(O)(O)O>O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[CH:16][C:15]([OH:19])=[O:18])[C:7]2=[O:13]
Reactant: O=C1CCCc2c(F)cc(F)cc21
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)C=C1CCc2c(F)cc(F)cc2C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 5,7-difluoro-3,4-dihydro-1(2H)-naphthalenone (3.2 g), glyoxylic acid monohydrate (1.6 g) and 85% phosphoric acid (3 ml) was heated with stirring at 90° C. for four hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to give (5,7-difluoro-3,4-dihydro-1-oxo-2(1H)-naphthalenylidene)acetic acid (4.2).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([F:10])=[CH:8][N:7]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([C:19]4[S:23][C:22]([C:24]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:25](OCC)=[O:26])=[N:21][CH:20]=4)[CH:15]=[C:16]([CH3:18])[CH:17]=3)[N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH:1]1([C:4]2[C:9]([F:10])=[CH:8][N:7]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([C:19]4[S:23][C:22]([C:24]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH2:25][OH:26])=[N:21][CH:20]=4)[CH:15]=[C:16]([CH3:18])[CH:17]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(O)(c1ncc(-c2cc(C)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1)C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cnc(C(O)(CO)C(F)(F)F)s2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
To a solution of ethyl 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (36 mg, 0.073 mmol) in tetrahydrofuran (10 mL) at −78° C. was added DIBAL-H (0.160 mL 0.160 mmol). After 30 minutes, the reaction mixture was warmed to 0° C. After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution, then diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-3,3,3-trifluoropropane-1,2-diol (3.5 mg, 0.001 mmol, 10%). MS ESI: [M+H]+ m/z 455.1. 1H NMR (500 MHz, DMSO-d6) δ 9.58 (bs, 1H); 8.38 (m, 1H); 8.06 (s, 1H); 7.89 (s, 1H); 7.43 (s, 1H); 7.07 (s, 1H); 3.99 (s, 2H); 2.29 (s, 3H); 2.28-2.23 (m, 1H); 1.18-1.14 (m, rhSYK activity=+++
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[CH3:35][CH:36]1[NH:40][C:39](=[O:41])[CH2:38][CH2:37]1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:40]5[C:39](=[O:41])[CH2:38][CH2:37][CH:36]5[CH3:35])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: CC1CCC(=O)N1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)cc2N2CCNC2=O)CC1
Yield: 26.9 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (239 mg) described in Preparation Example 236 and 5-methylpyrrolidin-2-one (74 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (67 mg) was obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=5)[N:19]=[CH:18][C:17]4=[O:27])[CH2:12][CH2:13]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3 mL of a chloroform solution containing 631 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 6 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=5:1], to give 400 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a brown solid.
Reaction SMILES: Cl.C(OC1C=CC(S(Cl)(=O)=O)=CC=1[C:15]1[NH:20][C:19](=[O:21])[C:18]2=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[N:16]=1)C>N1C=CC=CC=1.ClCCl>[CH3:28][C:22]1[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[C:18]=1[C:19](=[O:21])[NH:20][CH:15]=[N:16]2
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)c2c(=O)[nH]cnn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
110 mg (0.6 mmol) of 3-butylsydnoneimine hydrochoride are dissolved in 2.5 ml of pyridine and cooled to 0° C. 210 mg (0.5 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are added, and the reaction mixture is stirred for 2 hours at 0° C. and overnight at room temperature. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol) gives 16 mg (6%) of 2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Fe].C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCOCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(C(=O)CCCCOCc2ccccc2)cc1

Procedure:
A mixture of 23 g of formula (IX) compound obtained in the preceding example and 23 g of powdered iron in 200 ml of an aqueous solution of 10% ammonium chloride and 20 ml of ethanol was left under agitation for an hour at room temperature. Then it was extracted with methylene chloride, filtered, the filtrate was washed with water, dried on sodium sulfate, filtered, the filtrate was evaporated and the residue crystallized in a mixture of ethyl acetate and isopropylic ether. 18.6 g of the expected compound were obtained.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(S(C)(=O)=O)CC3)nc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.2 mL, 1.1 mmol), and methanesulfonyl chloride (0.007 mL, 0.009 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 97/3) to 26 mg of the title compound. (64% yield)
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19]SC1C(C2C=NC=CC=2)=NNC=1.CI>>[CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCCSc1nc[nH]c1-c1cccnc1
Solvent: CI
Product: CCCCCCSc1nc[nH]c1C1=CCCN(C)C1

Procedure:
3-(5-Hexylsulfanyl-3H-imidazol-4-yl]-pyridine (77) was converted to the title compound (76B) using the methodology described for the conversion of 21A to 22A (see Scheme 3) (the quarternization however was done at room temperature with a slight excess of CH3I). Yield: 70% (oil). LCMS (method A); Rt: 1.21 min, ([M+H]+=280). 1H-NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 6.40-6.29 (m, 1H), 3.45-3.41 (m, 2H), 2.79-2.72 (m, 2H), 2.59 (t, J=6 Hz, 2H), 2.45 (s, 3H), 2.41-2.37 (m, 2H), 1.55-1.49 (m, 2H), 1.38-1.31 (m, 2H), 1.30-1.19 (m, 4H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:18]1[CH:17]=[C:16]([CH3:25])[CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cccc(-c2c(C(C)O)oc(=O)c3ccccc23)c1
Yield: 55.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.52 g, 1.93 mmol), m-tolylboronic acid (0.45 g, 3.28 mmol), Pd(PPh3)4 (0.11 g, 0.096 mmol) and Cs2CO3 (0.81 g, 2.5 mmol) to afford the title compound (0.3 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([O:29]CC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1.[Na+].[H][H]>O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([OH:29])=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(N)=O)c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(N)=O)c1csc(N)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
In 10 ml of water is dissolved 200 mg of sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) as obtained in Example 132C, followed by addition of 200 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for one hour. The catalyst is filtered off, and under ice-cooling 27 mg of sodium hydrogen carbonate is added. The mixture is stirred for 5 minutes and washed with ethyl acetate. To the aqueous layer is added 30 ml of Dowex 50W (H-form) resin, and the mixture is stirred for 1.5 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure to about a half volume thereof. The residue is chromatographed on an Amberlite XAD-II (40 g) column, eluting with water and then 15% ethanol. The fractions including the desired product are combined and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: C(O)(=O)C.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>C[O-].[Na+]>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: CCC(=N)N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(O)cc(O)n1
Yield: 84.1 %

Procedure:
Using the procedure of Example 1, Part B1, 18.5 g (0.14 mole) of propionamidine acetate and 90 ml of 25% sodium methoxide were reacted with dimethyl malonate (0.14 mole) to provide 16.5 g (89.5%) of 4,6-dihydroxy-2-ethylpyrimidine according to Step (1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH2:54])[CH2:49]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH:54][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:49]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NCc5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 75 mg), HCl salt of N1-benzyl-1-(2-fluorobenzyl)cyclohexane-1,3-diamine (0.15 mmol, 52 mg), HATU (0.15 mmol, 57 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(benzylamino)-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was purified by column chromatography on silica gel.