Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:32]([C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:38]2[S:39][C:35]([C:32](=[O:34])[CH3:33])=[CH:36][CH:37]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2ccc(C(C)=O)s2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 95.3 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 374 mg (2.2 mmol) of 5-acetylthiophene-2-boronic acid provided 525 mg (95%) of the desired product as a cream colored solid. Electrospray Mass Spec 551 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][C:16]#[CH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C1C[O:21][CH2:20]C1>>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:1][CH:2]3[CH2:3][C:20](=[O:21])[CH:17]=[C:16]3[CH2:15]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1
Reactant: C#CCN(CC=C)S(=O)(=O)c1ccc(C)cc1
Reactant: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC3=CC(=O)CC3C2)cc1
Temperature: 65 °C
Yield: 33 %

Procedure:
To a suspension of the catalyst A precursor resin, shown above {24 mg, 0.025 mmol[Co2(CO)m]} in anhydrous THF(5 cm3) was added N-(2-propenyl)-N-(2-propynyl)-4-methylphenylsulfonamide (125 mg, 0.5 mmol) and the resulting mixture was heated to 65° C. under an atmosphere of CO (50 mbar). After 48 h the mixture was filtered, the resin was washed with THF (2×1 cm3) and the combined filtrates were concentrated in vacuo. 1H-NMR spectroscopy of the pale yellow residue indicated a 1:1 mixture of starting material and product and no by-products. Purification by flash chromatography (SiO2, 20% EtOAc/hexane) gave the title compound (46 mg, 0.167 mmol, 33%) as a white solid; mp 147-149° C.; vmax(CH2Cl2)/cm−1 3058, 1716, 1651, 1350, 1164, 1094, 673; δH (360 MHz)(CDCl3) 1.96-2.02 (1 H, m), 2.32 (3 H, s, CH3), 2.48-2.58 (2 H, m), 3.01-3.36 (1 H, m), 3.93-3.98 (2 H, m), 4.27 (1 H, d, J 16.5), 5.92 (1 H, s, C═CH), 7.28 (2 H, d, J 8, Ar-H), 7.66 (2 H, d, J 8, Ar-H); δC{1H} (90 MHz)(CDCl3) 21.6 (CH3), 39.8 (CH2), 44.0 (CH), 47.7 (CH2), 52.5 (CH2), 126.2 (CH), 127.5 (CH), 130.1 (CH), 133.7 (C), 144.2 (C), 178.6 (C), 207.2 (C═O).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].Cl>CC(C)=O.[OH-].[Na+]>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(NC(=O)c1ccccc1F)C(=O)O
Yield: 33.1 %

Procedure:
To a homogeneous solution of L-alanine(5 g, 56.1 mmol) in acetone (90 ml) and 1N NaOH (90 ml) was added 2-fluorobenzoyl chloride (8.9 g, 56.1 mmol) dropwise. Basicity of the reaction was maintained by adding 1N NaOH periodically. After the addition of 2-fluorobenzoyl chloride was completed, the reaction mixture was acidified to pH 2 using 1N HCl. The oil that precipitated out was extracted into EtOAc, which was dried over MgSO4, filtered, and concentrated to yield 2-(2-fluorobenzoylamino)propionic acid (intermediate XXIa, 3.92 g). Upon standing, more crystals of intermediate XXIa (2.3 g) precipitated from the acidic aqueous solution and were collected.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C(Cl)(=O)C.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12]>>[CH2:1]([O:4][C:10]([C@@H:11]([C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])=[O:9])[CH2:2][CH3:3]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CCCO
Solvent: CC(=O)Cl
Product: CCCOC(=O)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37.5 °C
Reaction time: 2.5 h
Yield: 73.4 %

Procedure:
3.917 kg (65 mol) of 1-propanol was placed in a reactor, and the temperature within the reactor was lowered to a temperature between −10° C. to 10° C. Then, 0.523 kg (6.7 mol) of acetyl chloride was added slowly thereto at a temperature between −10° C. to 35° C. To the solution, 1 kg (6.7 mol) of L-arabinose was added, and the mixture was warmed to 35-40° C. and stirred at that temperature for 2-3 hours, and then at 27-32° C. for 20 hours. After completion of the reaction, the solids were filtered and washed with 0.536 kg of 1-propanol. The filtered solids and 3.6 liters of dichloromethane were placed in a reactor and stirred for 1-2 hours. After this, 0.079 kg of pyridine was added thereto, and the mixture was stirred for 30 minutes, filtered, washed with 0.662 liters of dichloromethane, and then dried in a vacuum, thus obtaining 1.024 kg (80% yield) of 1-propoxy-L-arabinose. 1H NMR (D2O): δ 4.85 (d, 1H), 3.90 (m, 1H), 3.85-3.65 (m, 3H), 3.55 (m, 2H), 3.40 (m, 1H), 1.55 (m, 2H), 0.85 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:20]=[CH:21][CH:22]=[N:23]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2nccnc2c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5nccnc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoxaline-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoxaline.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][OH:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24](C)=[CH2:25]>ClCCl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][O:13][C:23](=[O:27])[CH:24]=[CH2:25])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC1CCC(CC(CC)CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC(CC)CC1CCC(CCC)CC1
Reaction time: 8 h

Procedure:
2-(4-propyl-cyclohexylmethyl)-butan-1-ol (13 g, 61.2 mmol) is dissolved in dichloromethane (50 ml) and triethylamine (3.5 ml) and a solution of methacryloyl chloride (2.2 ml, 21.8 mmol) in dichloromethane (30 ml) is added dropwise at 0° C. The reaction is stirred overnight, evaporated, filtered through silica with heptane/ethyl acetate (19:1) and the crude product is crystallised from ethanol to give acrylic acid 2-(4-propyl-cyclohexylmethyl)-butyl ester as a colourless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH2:11][C:12]#[N:13].[NH2:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([CH:22]=O)=[CH:17][N:16]=1>C(OCCO)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[C:11]1[C:12]([NH2:13])=[N:21][C:19]2[N:20]=[C:15]([NH2:14])[N:16]=[CH:17][C:18]=2[CH:22]=1
Reactant: N#CCc1c(Br)cccc1Br
Reactant: Nc1ncc(C=O)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
To a solution of 0.23 g 60% sodium hydride suspension in 11.0 mL of 2-ethoxyethanol was added 4.18 g of 2,6-dibromophenylacetonitrile and 2.00 g of 2,4-diaminopyrimidine-5-carboxaldehyde. The reaction was refluxed for 4 hours, cooled, and poured into ice water. The residue was washed well with acetonitrile then diethyl ether to give 3.62 g of 6-(2,6-dibromo-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 422=M+ +C2H5, 396 (Base), 394=M+ +H, 393=M+ ; mp 284°-289° C.
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.C(N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>ClCCl>[C:61]([N:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:2]([CH3:1])[C:3](=[O:45])[C:4]2[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][C:11]=3[C:22]3[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=4)[CH:25]=[CH:24][N:23]=3)=[O:8])[CH:5]=2)[CH2:49][CH2:50]1)(=[O:63])[CH3:62]
Reactant: CC(=O)Cl
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 34.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-isophthalamide (150 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (3 mL), and triethylamine (63 mg, 0.62 mmol, 3.00 equiv). This was followed by dropwise addition of acetyl chloride (25 mg, 0.32 mmol, 1.50 equiv) with stirring at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of sodium bicarbonate and 2×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (130 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 56.5 mg (38%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.96 (d, J=5.1 Hz, 1H), 8.70 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.16˜8.08 (m, 3H), 7.87˜7.86 (m, 1H), 7.79˜7.56 (m, 7H), 4.71 (s, 2H), 4.00˜3.89 (m, 5H), 3.63˜3.52 (m, 1H), 3.23 (s, 3H), 2.17 (s, 3H), 2.01 (s, 1H), 1.81 (d, J=4.8 Hz, 1H). MS (ES, m/z): 770 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:16]=O>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[CH2:16][NH:13][CH2:12][C:11]2([CH3:15])[CH3:14]
Reactant: COc1ccc(C(C)(C)CN)cc1OC
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(C)(C)CNC2
Yield: 80.2 %

Procedure:
A conventional alkylation reaction was carried out using a dimethylformamide solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile. A conventional catalytic hydrogenation reaction was carried out using an ethanolic solution (30 ml) of 1.75 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile, 3.0 ml of an aqueous 28% ammonia solution and 4.3 g of Raney nickel to give 1.59 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine. Then, a conventional cyclization reaction was carried out using a formic acid solution (8 ml) of 1.58 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine and 0.252 g of paraformaldehyde to give 1.34 g of 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline as a pale yellow oily substance. A conventional alkylation reaction was carried out using a solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile in dimethylformamide, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]I>>[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1
Reactant: COC(=O)Cc1ccccc1CI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: COC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (2-iodomethylphenyl)-acetic acid methyl ester analogous to Example 310, steps C and D.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[C:31]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.12 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamide dihydrochloride are initially charged in 0.3 ml of DMF, and 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After 16 h of stirring at RT, a further 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After a further 12 h of stirring at RT, the supernatant solution of the reaction mixture is purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a mixture of methanol and 4M HCl in dioxane, then reconcentrated and dried under high vacuum. 8 mg (17.1% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[Br:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2[nH]ccc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
7-Azaindole (2, 3.57 g, 30.2 mmol) was dissolved in tetrahydrofuran (240 mL) under an atmosphere of nitrogen. At −40° C., N-bromosuccinimide (5.38 g, 30.2 mmol) in tetrahydrofuran was added under an atmosphere of nitrogen. The reaction mixture was stirred for a few hours as it was gradually warmed to room temperature and the reaction was followed by TLC. The reaction was quenched with sodium thiosulfate pentahydrate (7.50 g, 30.2 mmol) in water (1M). Two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with anhydrous sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography (25-40% ethyl acetate in hexanes) to yield the desired product as a white solid, 3, (4.20 g, 21.3 mmol). MS(ESI) [M+H+]+=198.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9](Br)[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[N:6][N:7]=1.[CH:21]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Al](C)C>C[Si](C)(C)N[Si](C)(C)C.C1COCC1.Cl[Pd]Cl>[NH2:1][C:2]1[C:3]2[N:10]=[C:9]([CH3:21])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: Nc1nnnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: C[Al](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1nc2c(N)nnnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 310 %

Procedure:
The compound from Step A (112 mg, 0.3 mmol) was heated at reflux in hexamethyldisilazane (15 mL) for 16 hours. The mixture was evaporated to dryness to give a syrup which was dissolved in dry THF (12 mL). PPh3 (10 mg; 0.04 mmol), PdCl2 (3.5 mg; 0.02 mmol) and AlMe3 (100 μl; 0.94 mmol) were added. The mixture was reflux for 5 hours. The mixture was evaporated to dryness. The crude product was dissolved in methanol (30 mL) in the presence of ammonium chloride. The mixture was evaporated to dryness and the residue was purified on silica gel reverse-phase (C18) using water/acetonitrile (from 9/1 to 6/4) as eluant to give the title compound (35 mg) as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[CH2:9][CH2:8]1.N>Cl>[C:22]([C:20]1[CH:19]=[N:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:8][CH2:9]2)[CH:21]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: Cl
Agent: N
Product: O=C(O)c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Yield: 84.4 %

Procedure:
A mixture of 4.4 g (12.2 mmol) of ethyl 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-pyrazole-4-carboxylate in 50 ml of 2N HCl is refluxed for 4 hours. The mixture is cooled in an ice bath, neutralized with ammonia and extracted with chloroform. 3.4 g of 4-carboxy-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-pyrazole with a melting point of 104°-105° C. are thus obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([NH:24][C:12]([C:10]2[CH:9]=[CH:8][C:7]3[C:2](=[O:1])[N:3]=[C:4]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[S:5][C:6]=3[CH:11]=2)=[O:14])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
N,N′-carbonyldiimidazole (520 mg, 3.2 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (700 mg, 2.4 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, cyclopropylamine (700 mg, 12.2 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from diisopropyl ether-methanol to give the titled compound (45 mg, 5%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=O)=[CH:4][C:3]=1[Cl:17].[CH2:18]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:4][C:3]=1[Cl:17]
Reactant: CCCCN1CCC(CN)CC1
Reactant: CCCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(CCC)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-propylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 16, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]([C:9]1[N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:11]2[C:16]([C:17]=1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)=[CH:15][CH:14]=[C:13]([O:30]C)[CH:12]=2)=[O:8]>CCS.C(Cl)Cl>[F:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][NH:19][C:18]([C:17]1[C:16]2[C:11](=[CH:12][C:13]([OH:30])=[CH:14][CH:15]=2)[N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:9]=1[C:7]([OH:8])=[O:6])=[O:29]
Reactant: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC)cc2n1Cc1ccccn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(NCc1ccc(F)c(F)c1)c1c(C(=O)O)n(Cc2ccccn2)c2cc(O)ccc12
Reaction time: 2 h

Procedure:
General Procedure M. To a solution of AlCl3 (1.8 g, 13.5 mmol) in EtSH (25 ml) at room temperature was added a solution of methyl3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 1.26 g, 2.7 mmol) in CH2Cl2 (75 ml). The reaction was stirred for 2 h and was quenched with ice. The mixture was concentrated in vacuo, and the resulting white suspension in aqueous solution was acidified with 1M HCl and filtered. The cake was washed with H2O (×3), taken in MeOH, dried over MgSO4, and concentrated in vacuo to yield the title compound as a crude yellowish white solid contaminated with unknown inorganic product. The crude was used without further purification.
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]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([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]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)c(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].CO.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:23])=[CH:17][CH:16]=1
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 18.6 %

Procedure:
The method of Example 10 was followed with 2-butanesulfonamide (6.85 g), methanol (250 ml), sodium methoxide (2.7 g), tetrahydrofuran (250 ml) and 4-chlorophenyl isocyanate (7.7 g) with the resulting solid being recrystallized from ethyl acetate to give 2.7 g of white crystals with a melting point of 172°-174° C.