Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCCC1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCCC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (0.077 g, 0.19 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopentanecarboxylic acid ethyl ester (0.079 g, 0.23 mmol), and potassium carbonate (0.066 g, 0.48 mmol) were combined in 2:1 DME:H2O (3 mL). The solution was purged with N2 for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.02 mmol) was added. The mixture was purged with N2 for an additional 5 minutes, and then the reaction was stirred at 90° C. in a sealed tube for 1.5 hours. Aqueous work-up, followed by silica gel chromatography, provided the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](OC(C)(C)C)=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])C1C=CC=CC=1.F[C:54]1[C:59](O)=[C:58](F)[C:57](F)=[C:56](F)[C:55]=1F.C(Cl)CCl>ClCCl>[CH3:22][C@H:20]1[CH2:19][N:18]2[C@H:17]([C:15](=[O:16])[O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:42](=[O:43])[N:38]3[C@H:37]([C:35](=[O:36])[N:30]4[C@H:29]([C:27](=[O:28])[NH:26][C@@H:24]([CH3:25])[C:23]2=[O:49])[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:41][CH2:40][CH2:39]3)[CH2:21]1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)OCc3ccccc3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3.95 g (5.41 mm ol) of the acid from example 25A and 3.98 g (21.65 mmol) of pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to −20° C. under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is concentrated to dryness and the residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml). The mixture is stirred for 3 h and the solvent is subsequently removed in vacuo. The residue is dissolved in dichloromethane (about 900 ml) and slowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml). The reaction mixture is stirred overnight. The phases are separated, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC using acetonitrile/water (gradient). 1.98 g (60% of th.) of the product are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([O:16]CC)=O)[CH:8]=2)[NH:3]1.O.[NH2:20][NH2:21]>C(O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:20][NH2:21])=[O:16])[CH:8]=2)[NH:3]1
Reactant: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetate (0.4 g, 1.7 mmol) in ethanol (10 mL), hydrazine hydrate (0.9 g, 17 mmol) was added and the reaction was heated at 80° C. for two hours. The solid which formed was filtered and dried. 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetohydrazide was obtained as a white solid (0.25 g, 66%) and was used in the next step without further purification. 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=8.40 Hz, 2H), 4.31 (d, J=4.00 Hz, 2H), 4.41 (s, 1H), 6.76 (d, J=2.00 Hz, 2H), 6.82 (s, 1H), 9.26 (s, 1H), 9.91 (s, 1H). LCMS: RT 0.607 min. LCMS (ES-API), m/z 236.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 86.1 %

Procedure:
Using 4-bromo-2-fluorobenzoic acid (1.08 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.01 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.72 g) was obtained.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][CH2:13][C:14]([NH:11][CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CC12CCC(C1)C(C)(C)C2N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Reaction time: 12 h

Procedure:
To a solution of 1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine (5 g, 26.3 mmol) in methylene chloride (20 ml) and triethylamine (4 ml) was added chloroacetyl chloride (2.1 ml, 26.4 mmol) dropwise. The resulting solution was stirred for 12 hours, then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 10% ethyl acetate/hexane, to yield 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([OH:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[CH3:23][N:24]=[C:25]=[O:26].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([O:12][C:25](=[O:26])[NH:24][CH3:23])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Reactant: CN=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)OC(C(Oc1ccc(Cl)cc1Cl)n1cncn1)C(C)(C)CF
Yield: 86 %

Procedure:
8.4 g (0.024 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-ol were dissolved in 100 ml of dioxane, and 2 ml of methyl isocyanate and 3.5 ml of triethylamine were added. The mixture was heated under reflux for 10 hours and concentrated by distilling off the solvent in vacuo. The residue was heated in 50 ml of ethyl acetate and the mixture was filtered. 8 g (86% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-methylcarbamoyloxy-1-(1,2,4-triazol-1-yl)-butane were obtained in the form of colorless crystals of melting point 124°-27° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([O:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[N:10]=[C:9]([OH:11])[C:8]([O:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1
Reactant: CCCOc1ccc(CN=[N+]=[N-])nc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(CN)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-azidomethyl-2-benzyloxy-3-propoxy-pyridine (544 mg, 2.00 mmole), 12 mL of tetrahydrofuran, and triphenylphosphine (524 mg, 2.00 mmole) then water (540 □L, 30.0 mmole) is added and this is stirred at ambient temperature overnight. The reaction mixture is evaporated to dryness in vacuo and then washed with 2:1 hexanes/ethyl acetate and filtered. This resulting solid is taken up in ethanol and hydrogenated over 10% palladium on carbon at 1 atmosphere. The reaction mixture is filtered washed with ethanol, evaporated to give a brownish green solid, 93 mg, (25%), MS (ES+): m/z 183.3 (M+H). This is used as is for the next step.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)[CH2:37][CH3:38]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([O:39][CH2:36][CH2:37][CH3:38])[CH:45]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-propoxyphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[4-(2,4-dichloro-phenyl)-2-(3′-propoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: O1CCCC1.[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][N:7]=1.CC(C)([O-])C.[K+].[N:22](OC(C)(C)C)=[O:23]>O>[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11](=[N:22][OH:23])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)ON=O
Reactant: c1cc2c(cn1)CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: ON=C1CCCc2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a nitrogen atmosphere, tetrahydrofuran (125 mL) solution of 6.5 mL of 5,6,7,8-tetrahydroisoquinoline was added to tetrahydrofuran (100 mL) solution of 11.4 g of potassium tert-butoxide, and stirred at room temperature for 18 hours. Next, 17.5 mL of tert-butyl nitrite was dropwise added to the reaction liquid at 0° C., and stirred at room temperature for 18 hours. Saturated saline water was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was crystallized from water/ethanol to obtain 6.06 g of the entitled compound as a pale brown solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(O)=[O:2].P(Cl)(Cl)(Cl)=O.[NH3:32].Cl>CN(C)C=O>[C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=[O:2])[NH2:32]
Reactant: N
Reactant: CS(=O)(=O)Nc1cc2occ(C(=O)O)c(=O)c2cc1Oc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
3.75 g of 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 75 ml of N,N-dimethylformamide. Thereto was dropwise added 4.6 g of phosphorus oxychloride at -10° to -5° C. The mixture was stirred for 3 hours at the same temperature. The reaction mixture was dropwise added to 40 ml of a concentrated aqueous ammonia solution at 10°-20° C. The mixture was stirred for 30 minutes at the same temperature and then adjusted to pH 4 with 4N hydrochloric acid. The resulting crystal was collected by filtration, washed with water and recrystallized from acetic acid to obtain 2.81 g (yield: 75.1%) of 3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[OH-].[K+]>C(O)C.O>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:6]1[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-II) in ethanol was added potassium hydroxide in water and stirred overnight at room temperature. Solvent was removed under reduced pressure; the residue was taken in water and washed with diethyl ether. The aqueous layer was acidified with dilute HCl and precipitate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated to afford 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid (D1-III).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1COCCN1
Product: CC1(C)CN(CC(=O)N2CCOCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 86 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and morpholine in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29]([O:31]C)=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29]([OH:31])=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:33]([F:36])([F:34])[F:35])=[N:9]1
Reactant: COC(=O)c1cc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)ccc1-c1cccc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)O)c1
Yield: 77.5 %

Procedure:
A solution of methyl 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylate (1.37 g, 2.6 mmol) and NaOH (1 g, 25 mmol) in MeOH—H2O (2:1, 16 mL) was refluxed for 2 h. After cooling, solid was removed and the filtrate was acidified with formic acid. Solid was collected by filtration and washed with water and dried under high vacuum to afford 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylic acid (1.05 g). MS(ES): 521 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(OC)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(OC)cc1[N+](=O)[O-]
Yield: 40.5 %

Procedure:
By using 420 mg of N-(5-fluoro-4-methoxy-2-nitrophenyl)glycine ethyl ester, 420 mg of imidazole and 2.5 ml of DMF, 200 mg (41%) of N-[5-(1H-imidazol-1-yl)-4-methoxy-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([Br:15])[S:14][C:10]=2[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:15][C:13]1[S:14][C:10]2[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16][C:11]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2nc(Br)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2nc(Br)sc2C1
Reaction time: 4 h
Yield: 102.9 %

Procedure:
A solution of (2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.50 grams, 1.5 mmol, obtained in preparation 2) in dichloromethane (30 mL) was treated with trifluroacetic acid (1.1 mL, 15 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of the reaction, the mass was quenched with ice cold water and adjusted pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL) and the combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. The organic volatiles were evaporated under vacuum to obtain the title compound (0.36 grams).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.N1C=CC=CC=1>O>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3,5-dichlorobenzenesulfonyl chloride (0.256 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 2 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.355 g), mp 217-219° C.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[C:25]([NH:26][C:27]([C:29]2[C:37]3[N:36]=[C:35]([N:38]4[CH2:42][CH2:41][CH2:40][C@@H:39]4[C:43]4[C:44]([O:50]C)=[N:45][CH:46]=[C:47]([F:49])[CH:48]=4)N=CC=3NN=2)=[O:28])=[CH:24][CH:23]=[N:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>Cl.O1CCOCC1>[F:49][C:47]1[CH:48]=[C:43]([C@H:39]2[CH2:40][CH2:41][CH2:42][N:38]2[C:35]2[CH:19]=[CH:20][N:21]3[N:22]=[CH:23][C:29]([C:27]([NH:26][C:25]4[N:21]([CH2:20][CH2:19][OH:18])[N:22]=[CH:23][CH:24]=4)=[O:28])=[C:37]3[N:36]=2)[C:44]([OH:50])=[N:45][CH:46]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ncc2[nH]nc(C(=O)Nc3ccnn3CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccnn1CCO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Temperature: 100 °C

Procedure:
A suspension of (R)-N-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo pyrimidine-3-carboxamide (201 mg, 0.285 mmol) in 4M HCl in dioxane (6 mL) was sealed and heated to 100° C. for fours hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and washed with saturated NaHCO3 (5 mL), water (5 mL) and brine (5 mL). The organic layer was concentrated to give crude (R)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added THF (20 mL), DEAD (53.9 μL, 0.342 mmol) and triphenylphosphine (89.8 mg, 0.342 mmol). The reaction mixture was stirred for 18 hours, then concentrated under vacuum. The residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to afford the title compound (1.8 mg, 1.5% yield). MS (apci) m/z=435.3 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1.C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:21])=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@H](O)C2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol) and HATU (9.06 g, 23.82 mmol) were dissolved in DMF (75 ml) and allowed to stir for 5 min at room temperature before adding ammonium chloride (4.25 g, 79 mmol) and DIEA (13.87 ml, 79 mmol). The reaction turned yellow upon addition of the base. The reaction was allowed to stir at room temperature for 1 h then partitioned between water and ethyl acetate. The organic layer was washed once with brine before drying over sodium sulfate, filtering, and concentrating to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (4.19 g, 14.84 mmol, 93% yield) as an off-white solid. MS (ESI) m/z 283.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1>C(O)(=O)C>[CH3:20][C:19]1[CH:18]=[C:17]2[C:16](=[CH:15][C:14]=1[CH3:13])[N:22]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[C:5]1=[N:21]2
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CC(=O)O
Product: Cc1cc2nc3[nH]c4ccc(Br)cc4c3nc2cc1C

Procedure:
A mixture of 22.6 g 5-bromoisatin (0.1 mole), 15.0 g 4,5-dimethyl-o-phenylene diamine (0.11 mole) and 400 ml acetic acid is boiled under reflux for 4 hours. After cooling the product is sucked, washed with ethanol and dried. Yield 29 g, 89%. Recrystallisation from pyridine gives needle shaped crystals with melting point 319°-322° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccccc1Br
Product: C[C@@H](CCl)COc1ccccc1Br

Procedure:
Prepared by Procedure U and Scheme AK using 2-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.