Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH3:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:19][C:20]1[N:1]=[C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]=1[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc2ccccc2c1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3ccccc3c2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a stirred solution of 32 mg (0.13 mmol) (2-amino-benzo[b]thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.09 ml (0.13 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 21 mg (52%) (2-methyl-4-phenyl-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1ccc(Br)cc1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-bromo-4-fluorobenzene
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH:31]([CH3:33])[CH3:32])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:25][C:26]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.36 g), 4-bromo-2-isopropylphenol (0.3 g) in DMF (8.0 mL) was added potassium carbonate (0.5 g) and PdCl2dppf (60 mg) under nitrogen. The mixture was stirred at 80° C. for 16 h. The reaction was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product tert-butyl 4-(4-hydroxy-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.12 g) was obtained by Combiflash.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1C=C[N:10]=[C:11]2Cl.C([O-])([O-])=O.[K+].[K+]>O>[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:2]=[CH:1][N:4]=[C:11]2[NH2:10]
Reactant: CC(N)=O
Reactant: Clc1nccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nccc2c(Br)cccc12
Temperature: 25 °C

Procedure:
Acetamide (4.9 g, 82 mmol), 5-bromo-1-chloroisoquinoline (1.00 g, 4.1 mmol) and K2CO3 (2.8 g, 21 mmol) were combined in a sealed tube and the mixture heated at 200 C for 1.5 h. The mixture was allowed to cool to rt and the solid residue suspended in 400 mL water. The brown solid was collected as the title compound (750 mg). MS (ESI pos. ion) m/z: 223 (MH+). Calc'd exact mass for C9H7BrN2: 223.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([NH:9][CH2:10][CH2:11][OH:12])[CH:8]=1>[Pd].CCO>[NH2:13][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][CH2:10][CH2:11][OH:12]
Reactant: COc1ccc([N+](=O)[O-])c(NCCO)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(NCCO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round bottom flask, 2-((5-methoxy-2-nitrophenyl)amino)ethanol (1.43 g, 6.74 mmol), Pd/C (150 mg) and EtOH (30 mL, degassed) was added. The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 18 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure to yield 2-((2-amino-5-methoxyphenyl)amino)ethanol as a red solid which was used as such without further purification. LC-MS conditions B: tR=0.30 min, [M+H]+=183.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
To a mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.150 g, 0.37 mmol) in THF (4 ml) at −78° C. was added LDA (0.247 mL, 0.50 mmol, 2 M in THF). After stirring for 10 min at −78° C., ethyl bromoacetate (0.061 mL, 0.55 mmol) was added. The mixture was then warmed to rt for 10 min and quenched with sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography (SiO2 with a gradient elution of 0-60% EtOAc/hexanes) to afford ethyl 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoate (0.120 g, 83%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(CCl)cc1

Procedure:
A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml of thionyl chloride is stirred at room temperature for 25 hours after which the excess thionyl chloride is removed under vacuum to yield p-chloromethylphenylacetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:11](N)(N)(=[O:13])=[O:12].N1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][S:11](=[O:13])(=[O:12])[N:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1c2cc(Br)ccc2NS1(=O)=O
Temperature: 125 °C
Reaction time: 14 h

Procedure:
To a round bottom flask was added 4-bromo-N2-methylbenzene-1,2-diamine (1-2) (9.07 g, 45.1 mmol), sulfamide (8.84 g, 92 mmol), and finally anhydrous pyridine (75 mL). The reaction mixture was then heated to 125° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 14 hours. The crude reaction mixture was then allowed to cool to room temperature, suspended in ethyl acetate and added 6N HCl until pH <3. Crude mixture was then filtered. Filtrate organics were separated, then washed with 6N HCl twice dried over sodium sulfate, filtered, and concentrated to give 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3). HRMS (M+H)+: observed=262.9486, calculated=262.9484.
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+]>O.CCOC(C)=O>[O:9]=[C:8]1[O:10][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a solution of L-glutamic acid (10.07 g, 0.068 mol, J&K CHEMICA) in 20 ml of concd. HCl and 40 mL H2O was added a solution of NaNO2(7.0 g, 0.102 mol, Shantou Xilong chemical factory) in H2O (20 mL) slowly at −5° C. The mixture was continued to stir for 12 hrs at room temperature. The reaction mixture was evaporated in vacuo below 50° C. to give yellow oil, which was dissolved in EtOAc. The solid formed was filtered and washed with EtOAc. The filtrate and washing solution were combined, dried over Na2SO4. The solvent was concentrated in vacuo to give (S)-tetrahydro-5-oxofuran-2-carboxylic acid as pale yellow oil (8.1 g, 91.6%)1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16](C)CCCN=C=NCC.ON1C(=O)CCC1=O.[OH-].[NH4+].Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:11](=[O:12])[NH2:16])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
(R)-3-(tert-Butoxycarbonylamino)-2-methylpropanoic acid (465 mg, 2.3 mmol) was dissolved in dichloromethane (11 ml). 4-Dimethylaminopyridine (280 mg, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (877 mg, 4.58 mmol) were added, followed by N-hydroxysuccinimide (290 mg, 2.52 mmol). After 4 h of stirring at room temperature, concentrated ammonium hydroxide (1.6 ml) was added slowly. The reaction mixture was stirred for an additional 20 min then aqueous HCl and ethyl acetate were added and the aqueous layer was extracted six times with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography to give 335 mg (72%) of ((R)-2-carbamoyl-propyl)-carbamic acid tert-butyl ester. (M+Na)+=225.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28](OC)=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[OH:29][CH2:28][C:26]1[CH:27]=[C:22]2[N:21]=[CH:20][N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[C:23]2=[N:24][CH:25]=1
Reactant: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a stirred mixture of methyl 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (76 mg, 0.174 mmol) from Example 79 in anhydrous DCM (1 mL) at −50° C. under argon was added dropwise diisobutylaluminum hydride (1 M solution in DCM, 0.696 μL, 696 mmol). The mixture was allowed to warm to −20° C. and stirred for 10 min. The reaction mixture was acidified to pH˜1.0 with 2 M aq HCl, and the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.35 (d, J=1.3 Hz, 1H), 7.93-8.01 (m, 2H), 7.65 (s, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 5.47 (s, 2H), 5.29 (br s, 1H), 4.75 (d, J=4.0 Hz, 1H), 4.62 (br s, 2H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.35 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32](O)=[O:33])[CH2:29][N:30]=1)=[CH:9]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:57][NH:58][CH2:59][CH2:60][OH:61]>O.CN(C)C=O>[OH:61][CH2:60][CH2:59][N:58]([CH3:57])[C:32](=[O:33])[CH2:31][CH:28]1[S:27][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[N:30][CH2:29]1
Reactant: CNCCO
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)N(C)CCO)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol (100 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (140 mg), 2-(methylamino)ethanol (60 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (140 mg, yield 50%) as colorless crystals. melting point 94-96° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The reaction was carried out under argon. Allyl 4-[4-cyano-2-(phenylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (220 mg, 0.378 mmol) and morpholine (1.5 eq., 43 mg, 0.567 mmol) were initially charged in dry THF (6 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 22 mg, 0.019 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed successively with 0.1 N hydrochloric acid (6 ml), saturated ammonium chloride solution (3×50 ml), water (30 ml) and saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The target product was obtained as a solid (104 mg, 51% of theory).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(#N)C.O1CCOCC1.O>[F:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[C:20]([C:18]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:10][C:8]([C:6]3[N:7]=[C:3]([CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[S:4][CH:5]=3)=[O:9])[CH:19]=2)[CH:28]=1
Reactant: O=C(Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCCCC2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a suspension of 2-(chloromethyl)-N-[6-(6-fluoro-1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.088 mmol) in acetonitrile (2 ml) was added piperidine (0.02 ml, 0.18 mmol) and the mixture was heated to 80° C. for 2 hours. Further piperidine (0.02 ml, 0.18 mmol) was added and heating was continued at 80° C. for 30 mins. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in MeOH and 2M aqueous NaOH (5 ml, 1:1, v.v) and stirred at room temperature for 1 hour, then neutralised with 2M aqueous HCl to ˜pH=5 and extracted with DCM (3×5 ml). The extracts were combined and the solvent removed under a stream of nitrogen. The residue was taken up again in MeOH and 2M aqueous NaOH (5 ml, 1:1, v/v) and stirred at room temperature for 3 hours. The mixture was neutralised with 2M aqueous HCl to ˜pH=7 and the MeOH was blown off under a stream of nitrogen. A precipitate was observed which was collected by filtration, then dissolved in 1 ml DMSO/MeOH (1:1) and purified by MDAP (Method B). The product-containing fractions were blown down under a stream of nitrogen to give a clear oil which was dissolved in dioxane/water (2 ml, 1:1, v/v) and freeze dried to give the title compound as a white solid (10 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:51][CH:52]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[CH2:53][CH2:54][CH2:55][OH:56].C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:63][C:60]1[CH:59]=[CH:58][C:57]([CH:52]([NH:51][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:53][CH2:54][CH2:55][OH:56])=[CH:62][CH:61]=1
Reactant: NC(CCCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 4-amino-4-(4-chlorophenyl)butan-1-ol (Intermediate 16) (83 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 ml, 0.50 mmol) in DMF (2.0 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours then quenched in water (10 ml) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 67.4%) as a cream solid, which was used without further purification.
Reaction SMILES: [C:1]([C:6]([S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:8])[CH3:7])([O:3]CC)=[O:2].O.O1CCCC1.[OH-].[K+]>C(O)C>[C:1]([C:6]([S:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)([CH3:7])[CH3:8])([OH:3])=[O:2]
Reactant: CCOC(=O)C(C)(C)SCc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CSC(C)(C)C(=O)O)cc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Dissolve 2-(carboethoxy)-2-(4-methoxybenzylthio)propane (1.05 g, 3.91 mmol)in a mixture of 95% ethanol (18 mL), water (9 mL) and tetrahydrofuran (10 mL). Add potassium hydroxide (1.4 g, 25 mmol) and stir at room temperaturefor 2 hours then at 55° C. for 1 hour. Evaporate the solvent in vacuo and partition between water (50 mL) and ether (50 mL). Acidify to pH1 with concentrated hydrochloric acid and extract into methylene chloride (50 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give 2-(carboxy)-2-(4-methoxybenzylthio)propane as a tan solid (763 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](Cl)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCCC1=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Reactant: NC1CCCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-c2nc3c(c(NC4CCCC4)n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.265 g of 2-(4-chlorophenyl)-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, 0.4 g of cyclopentylamine and 1 ml of N-methylpyrrolidone were heated to 130° C. in an oil bath. After 5 hours, the mixture was diluted with 20 ml of water and stirred at room temperature. The precipitated product was filtered off with suction, washed with water and dried in vacuo at 40° C. Yield: 0.26 g. M.p.: 167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]#[N:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]([NH2:19])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3c(C#N)cccc3s2)cc1
Reactant: O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3s2)cc1

Procedure:
A mixture of EXAMPLE 1D (0.8 g) in polyphosphoric acid (8 mL) was stirred at 100° C. for 3 hours. The mixture was cooled, treated with water and extracted with dichloromethane. The solid that precipitated out of the organic layer was filtered, washed with water and dried to afford the title compound. 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.18-8.21 (m, 1H), 8.11-8.14 (m, 2H), 7.94 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.15-7.19 (m, 2H), 3.89 (s, 3H).