Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[CH3:28][C:29]1[C:30]2[CH:44]=[CH:43][CH:42]=[CH:41][C:31]=2[S:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:12]2[N:13]([C:14]([NH2:17])=[N:15][C:16]3[N:8]([CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH2:34][C:33]5[S:32][C:31]6[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=6[C:29]=5[CH3:28])[CH2:36][CH2:37]4)[CH:9]=[CH:10][C:11]=32)[N:18]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Cc1c(CN2CCNCC2)sc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN2CCN(CCn3ccc4c3nc(N)n3nc(-c5ccco5)nc43)CC2)sc2ccccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 1-[(3-methylbenzo[b]thiophen-2-yl)methyl]piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 2-(furan-2-yl)-7-(2-(4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=513.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.32 (s, 3H), 2.50 (m, 8H), 2.69 (t, 2H, J=6.4 Hz), 3.72 (s, 2H), 4.23 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 7.15 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.50 (br s, 2H), 7.68 (d, 1H, J=7.6 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=0.8 Hz).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Cc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Cc2ccccc2)c1Br
Yield: 24 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 by reacting 2-chlorosulfonyl-3-benzylthiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p. 180°-183° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:18][CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:34])[CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:18]([CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21](=[O:34])[CH2:20]1)=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (2.48 g, 0.0144 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-hexylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (4.0 g, 0.012 mol) in dichloromethane (50 ml) at -60° C. Stirring was continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ethyl acetate to give the title compound as white crystals, 920 mg, (22%), m.p. 154-5° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][C:10]([NH:12][C@:13]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:11]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[O:51]=[S:2]1(=[O:1])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][C:10]([NH:12][C@:13]12[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:49])[CH3:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:11]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 6 h
Yield: 76.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (15 mg, 0.021 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) under a N2 (g) atmosphere was added palladium hydroxide on carbon (3.67 mg, 5.23 μmol). The reaction mixture was purged with H2 (g) and was stirred under a H2 (g) atmosphere. After 6 h, the reaction mixture was filtered and washed with DCM and concentrated to give brown solid. The material was then plugged through a silica gel column (3 g), eluted with 90:10 DCM:MeOH, concentrated and dried to give 4-((1S,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-(2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)acetamido)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (11.5 mg, 76% yield) as a light brown solid. LC/MS: m/e 719.3 (M+H)+, 2.61 min (method 3). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.90 (d, J=7.3 Hz, 2H), 7.30-7.21 (m, 1H), 7.18 (d, J=7.3 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 4.09 (br. s., 1H), 3.77 (br. s., 1H), 3.65 (d, J=6.6 Hz, 2H), 2.59 (d, J=12.7 Hz, 4H), 2.32 (d, J=11.2 Hz, 1H), 2.13 (dd, J=17.0, 5.7 Hz, 1H), 1.97-1.82 (m, 3H), 1.78-1.67 (m, 3H), 1.60-1.42 (m, 12H), 1.39 (br. s., 1H), 1.24 (br. s., 4H), 1.13 (br. s., 1H), 1.07 (br. s., 3H), 1.00 (br. s., 6H), 0.92 (br. s., 6H), 0.88 (d, J=6.4 Hz, 3H), 0.78 (d, J=6.4 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=O)[NH:9][N:10]=1.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[NH:21][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[N:22][C:16]=2[CH:15]=1
Reactant: O=Cc1cc(-c2cccs2)n[nH]1
Reactant: Cc1cc(N)c(N)cc1C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2nc(-c3cc(-c4cccs4)n[nH]3)[nH]c2cc1C

Procedure:
Starting with 16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde, 12.4 mg of 4,5-dimethyl-1,2-phenylenediamine, and 17.3 mg of sodium metabisulphite, in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica and a purification by LC-MS, 5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole is obtained in the form of a white powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([CH2:25][OH:26])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)(Cl)Cl>[OH:5][CH:6]([CH2:25][OH:26])[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Acetyl chloride (1.15g. 14.8 mmoles) was added dropwise to a reactor containing N-(2,3-dihydroxypropyl)-hexadecylamine (1.5 g, 4.3 mmoles) in 3 mL of chloroform. The reaction was stirred for 16 hours at room temperature. When the reaction was completed, the, mixture was concentrated, ethanol and water was added, and the pH of the reaction was adjusted to 14. This mixture was extracted with chloroform, and organic layer was collected and concentrated. The sample was purified on a silica column chromatography to give 0.4 g of product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCN>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COc1ccccc1CCN
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(2-methoxyphenyl)ethylamine (0.62 g, 4 mmol) in dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.9 g (66%) of the title product:
Reaction SMILES: [SH2:1].[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:5]2[CH2:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18](=[S:1])[NH2:19])=[C:5]2[CH2:4]1
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1Cc2c(C(N)=S)ncn2-c2ccccc2C1=O
Reaction time: 48 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was passed for 1 hr. through a solution of 10.2 g (0.429 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 250 ml of pyridine and 2.5 ml of triethylamine. The green solution was left to stand for 48 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.0 g (87%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. A sample was recrystallized from methanol and gave pale yellow crystals; m.p. 295-297°.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[NH:31][N:30]=[CH:29]3)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:35][C:33]1[CH:34]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=[C:28]2[C:32]=1[NH:31][N:30]=[CH:29]2
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2cn[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2cn[nH]c12

Procedure:
60 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 60 mg (0.23 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-1H-indazole and 100 μL (0.58 mmol) DIPEA in 0.8 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous saturated NaHCO3 solution. The precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH2:11])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH:11][CH3:19])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c(N)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNc1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Yield: 59.3 %

Procedure:
Into a flask containing 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol, 1 equiv) is added DMF (15 mL, 0.2 M) before adding cesium carbonate (1.4 gm, 4.17 mmol, 1.5 equiv.) and idomethane (260 μL, 4.17 mmol, 1.5 equiv). After an hour, the reaction was quenched with water and the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (615 mg, 60%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][NH:24][C:23]([CH3:27])([CH3:26])[C:15]=3[N:16](C(OCC)=O)[N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[F:38][C:39]1([C:46](Cl)=[O:47])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>C1COCC1>[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][N:24]([C:46]([C:39]4([F:38])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[O:47])[C:23]([CH3:26])([CH3:27])[C:15]=3[NH:16][N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4]
Reactant: CCOC(=O)n1nc(Nc2nc(OCC)ncc2F)c2c1C(C)(C)NC2
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)C2(F)CCN(C)CC2)C3(C)C)n1
Temperature: 65 °C

Procedure:
To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (120 mg, 0.27 mmol) in 15 mL THF containing diisopropylethyl amine (0.23 mL, 4 eq) was added a 5 mL THF suspension of 4-fluoro-1-methylpiperidine-4-carbonyl chloride (128 mg, 2.6 eq). After heating for 5 hours at 65° C., the reaction was concentrated to dryness and carried on without further purification. To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-5-[(4-fluoro-1-methylpiperidin-4-yl)carbonyl]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate in methanol was added 2 mL of a 10% sodium hydroxide solution in methanol. After removing the solvent in vacuo, the residue was purified as in Example K1 above. See Table 1 below for NMR data.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH:11]([S:10][CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CSC
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Cl)SC
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
N-Chlorosuccinimide (5.97 g, 44.71 mmol) was added portionwise to ethyl (methylthio)acetate (6.00 g, 44.71 mmol) in carbon tetrachloride (30 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oil was purified by distillation to give 3.22 g (43%) of ethyl chloro(methylthio)acetate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 6.10 (s, 1H), 4.20 (q, J=7 Hz, 2H), 2.24 (s, 3H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)C.Cl[CH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2>O1CCCC1>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: [Mg]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 11.4 g of magnesium shavings, 151.5 g of diethyl malonate and 300 ml of dry ethanol is warmed to 60° under argon over a period of 30 minutes. After the vigorous reaction has faded, the mixture is heated to boiling under reflux for an additional 1 hour and then concentrated in vacuo. The residue is treated twice with 300 ml of dry benzene each time and in each case evaporated well. The residue obtained is dissolved under argon in 350 ml of dry tetrahydrofuran. Thereto there is added dropwise at room temperature over a period of 20 minutes a solution of 195.5 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 500 ml of dry tetrahydrofuran. The mixture is heated to boiling under reflux overnight while stirring and then evaporated in vacuo. The residue obtained is partitioned between 2.0 l of toluene and 500 ml of ice-water. The organic phase is washed successively twice with 500 ml of 1N hydrochloric acid each time, twice with 500 ml of water each time, twice with 250 ml of saturated sodium bicarbonate solution each time and several times with water, dried over magnesium sulfate and evaporated in vacuo. Diethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonate is obtained as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 0 %

Procedure:
To a solution of 4-phenoxyphenol (1.0 g, 5.4 mmol) in N,N-dimethylformamide (20 mL) were added 4-fluorobenzaldehyde (0.67 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.4 mmol), and the mixture was stirred at 100° C. for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (1.4 μg, yield 89%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:4]=1.FC(F)(F)[C:20]([OH:22])=[O:21]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[N:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(-n2ccc(C(F)(F)F)n2)cc1
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)cc1

Procedure:
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide: 3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-t-butylaminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (0.66 g) was dissolved in trifluoroacetic acid (20 mL) and heated at reflux for 30 min. The reaction was evaporated, then dissolved in ethyl acetate and washed with 1N sodium hydroxide solution (2×) and brine. This solution was dried and evaporated to 0.48 g of crude product. This material was made analytically pure by first subjecting it to flash chromatography with a 200 g column of silica gel and elution with 2:1 hexane:ethyl acetate and finally recrystallizing the homogeneous chromatography product from chloroform. There was obtained 0.262 g of the title compound; mp: 237.3; CHNSF: theory %C, 55.81, %H, 3.718, %N, 10.85, % S, 6.218, %F 11.03; found %C, 56.02, %H, 3.77, %N, 10.51, % S, 5.84, %F, 11.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of N2-(3-chlorophenyl)pyridine-2,3-diamine (29 mg, 0.13 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (27 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol), 4-methylmorpholine (32 μL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) in DCM (5 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting {(S)-1-[2-(3-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (44 mg), was dissolved in AcOH (3 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (35 mg, 72% over two steps). LCMS (Method C): RT 3.34 min [M+H]+ 373.2.