Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)Cc1cccc(O)c1
Product: O=C(Cc1cccc(O)c1)Nc1ccc(F)cc1
Yield: 88.6 %

Procedure:
The title compound was prepared as described in Example 44.A, using 3-hydroxyphenyl acetic acid (80 g, 0.52 mol) and 4-fluoroaniline (49.3 ml, 0.52 mol) to provide the title compound (113 g, 89% yield): ES-MS (m/z) 246 [M+H]+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:19]#[N:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23].CO[Na].CO>>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:21][C@@H:22]([CH3:23])[C:24]([OH:26])=[O:25])=[O:7])[N:9]=1)#[N:20]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccccc2c1O
Agent: CO[Na]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(C#N)c2ccccc2c1O)C(=O)O
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (135 mg, 0.5 mmol, see Example 1(a)), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in methanol (5 mL, 2.5 mmol) was heated in a microwave oven with stirring for 40 min at 120° C. before the mixture was concentrated in vacuo. To the residue was added water (10 mL) and the mixture was washed with diethyl ether (4×40 mL). The pH of the purified solution was adjusted to about 2 by the addition of aqueous 6 N HCl. The resulting suspension was extracted with ethyl acetate (1×40 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (101 mg); MS-(−)-ion: M−1=284.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M65) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (269 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21](OCC(Cl)(Cl)Cl)=[O:22])([CH3:11])[CH3:10]>C1COCC1>[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21]([O:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1)=[O:22])([CH3:11])[CH3:10]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
NaH (0.40 g, 10.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (20 mL), cooled to 0° C. and (S)-3-hydroxytetrahydrofuran (0.88 g, 0.68 mL, 10.0 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (3.30 g, 10.0 mmol, 70% pure) in THF (60 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (S)-3-hydroxytetrahydrofuran in THF were added after 5 and 29 h, respectively. After 2 d the is reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 30% to 60% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3S)-tetrahydro-furan-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (34.8 mg, 1.1%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8](Cl)[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(O)(C)C.[NH3:16]>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([NH2:16])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: N
Reactant: Clc1ncc2scc(Br)c2n1
Solvent: CC(C)O
Product: Nc1ncc2scc(Br)c2n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (1.0 g, 4.03 mmol) was dissolved in 2.0 M ammonia isopropanol (10 mL) and stirred at 100° C. for 48 hours in a sealed reactor. The reaction mixture was cooled to room temperature and then concentrated. Purification by chromatography (50% ethyl acetate/hexane) yielded a brown solid compound (560 mg, 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)c(F)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the suspension of 4-(2,4-difluoro-phenyl)-1H-indole (6.42 g, 28 mmol) in t-BuOH:ethanol:acetic acid (177 mL:105 mL:55 mL) was added pyridinium tribromide (27 g, 84 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (136 mL). Zinc dust (9.8 g, 150 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 5.16 g (75%) of 4-(2,4-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[CH2:19]([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: C#CCCCO
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: C#CCCCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 109° C. and MS: m/e=321.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and pent-4-yn-1-ol.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=[O:5].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1.[OH-].[K+]>CN(C)C=O.C(O)(=O)C>[CH2:2]([O:3][C:4]([C:6]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH2:7][CH2:8][CH2:9][C:10]1=[O:11])=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)Cc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A mixture of 9.4 g of ethyl 2-cyclopentanonecarboxylate, 10.6 g of ethyl p-chloromethylphenylacetate, 3.58 g of potassium hydroxide and 60 ml of dimethyl formamide was stirred at room temperature for 5 hours, at 50° C. for 1 hour and thereafter at room temperature overnight. The reaction mixture was acidified by addition of acetic acid, dimethyl formamide was removed by distillation, water was added to the residue, and the mixture was extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent evaporated to give an oily substance, which was subjected to a vacuum distillation affording 12 g of the desired compound, b.p. 180°-190° C. at 0.8 mm Hg.
Reaction SMILES: [Cl:1][C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([Cl:22])[CH3:21])=[CH:15][CH:14]=2)Br)=[CH:7][CH:6]=1)=[O:4].ClC(C)(C)C(C1C=CC(C(C2C=CC(C(=O)C(C)(Cl)C)=CC=2)(Br)Br)=CC=1)=[O:30]>>[Cl:1][C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([Cl:22])[CH3:21])=[CH:15][CH:14]=2)=[O:30])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(Cl)C(=O)c1ccc(C(Br)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Reactant: CC(C)(Cl)C(=O)c1ccc(C(Br)(Br)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Product: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1

Procedure:
492.6 g of oil are recrystallised from 300 g of cyclohexane, followed by filtration and washing. 134 g of white crystals are obtained. From the mother liquor there are obtained, by means of concentration, a further 356 g of yellow crystals, which are recrystallised from 300 g of cyclohexane, filtered and washed with 100 g of cyclohexane. 200 g of yellowish crystals are thereby obtained. From the next mother liquor there are obtained, by means of partial concentration, a further 16.1 g of white crystals, and 112.4 g of dark-yellow oil remain. Unfortunately, all those crystal fractions of bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-bromomethane are, according to the 1H NMR spectrum, mixed with the subsidiary product bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-dibromomethane (the first fractions to the greatest extent). The product has been over-brominated in this experiment. The subsidiary product is expected to give rise to bis[4-(2-chloro-2-methyl-propionyl)-phenyl]-methanone during hydrolysis.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=O)[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH2:2][O:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:28][C:24]2([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:31]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O=C(N1CCCC(O)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)(F)c1cc(COC2CCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following the procedure described in Example 72, 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene was used to alkylate 56 mg (0.19 mmol) of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxy-piperidin-1-yl)-methanone, forming the ether adduct [3-(3,5-Bis-trifluoromethyl-benzyloxy)-piperidin-1-yl]-[1-(4-chloro-phenyl)-cyclobutyl]-methanone (39 mg, 39%). A portion of this compound (22 mg, 0.043 mmol) was dissolved in 1 mL of THF and excess lithium aluminum hydride (16 mg, ca. 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, the suspension was stirred at room temperature for 30 minutes, and then was filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 3-(3,5-Bis-trifluoromethyl-benzyloxy)-1-[1-(4-chloro-phenyl)-cyclobutylmethyl]-piperidine, 189, was obtained (12 mg, 56%). Data for this compound: MS 506 (M++1).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]2[C:22](=[O:23])[C:21](=[O:24])[C:20]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:26]2)[CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:10][CH2:9][C@@H:8]([NH:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:26]1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CNC(=O)OC(C)(C)C)CC3CCCCC3)c(=O)c2=O)C1
Solvent: O=C(O)C(F)(F)F
Product: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CN)CC3CCCCC3)c(=O)c2=O)C1
Yield: 56.2 %

Procedure:
tert-butyl (2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate (17.4 mg, 0.03 mmol) was treated with neat TFA for 30 min. TFA was removed in vacuo, and the residue was purified by HPLC to give 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione (8.7 mg, 60%) as a TFA salt. 1H NMR (CD3OD) δ 0.8-2.1 (20 H), 3.0 (1 H), 3.1 (1 H), 3.25 (s, 3 H), 3.3 (m, 6 H), 3.5 (2 H), 4.45 (d, 1 H), 4.63 (m, 1 H), 7.15 (1 H), 7.21 (1 H), 7.35 (1 H), 7.40 (1 H). MS ESI +ve m/z 516 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:30][CH3:31])([CH3:28])[CH3:29])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:26]4[CH2:29][CH2:28][CH2:27]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Temperature: 100 °C

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (2.50 g, 5.77 mmol, Intermediate 4: step c), azetidine (988 mg, 17.3 mmol), and DMF (30 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The vessel was then cooled and contents were transferred to a separatory funnel with EtOAc dilution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% hexane/ethyl acetate) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][NH:19][CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][N:19]([CH2:34][C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:25]([CH3:24])[CH:26]=4)[CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cc(CN2CC3CN(CCNS(=O)(=O)c4ccc(C#N)cc4)CC(C2)O3)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
A mixture of 4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide (0.101 g, 0.30 mmol) and 1-methyl-1H-indole-3-carbaldehyde (0.081 g, 0.51 mmol) in 1,2-dichloroethane (4 mL) was agitated for 1.5 hours at room temperature. Sodium triacetoxyborohydride (0.216 g, 1.02 mmol) was added and resulting mixture was agitated over night at room temperature. An aqueous solution of Na2CO3 (3 mL) was added and the aqueous layer was extracted with dichloromethane (3×4 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 76 mg (52.8%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32][CH2:31]3)[CH:27]=[N:26][CH:25]=2)[CH:6]=[C:5]([O:44][CH3:45])[N:4]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[N:29]=[C:28]([N:30]3[CH2:31][CH2:32][CH:33]([NH2:36])[CH2:34][CH2:35]3)[CH:27]=[N:26][CH:25]=2)[CH:6]=[C:5]([O:44][CH3:45])[N:4]=1
Reactant: COc1cc(-c2ccc3c(c2)c(-c2cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n2)nn3C2CCCCO2)nc(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3[nH]nc(-c4cncc(N5CCC(N)CC5)n4)c3c2)nc(OC)n1
Temperature: 85 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-(2,6-dimethoxypyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (141 mg, 0.229 mmol) in DCM (1 mL) and TFA (0.5 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 85° C. for 20 min. The solvent was then removed and the residue was purified with RP-HPLC to give 1-(6-(5-(2,6-dimethoxypyrimidin-4-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine as a solid. MS (ESI, pos. ion) m/z: 433 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:20]1[C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[C:24]([Cl:31])[CH:23]=[C:22]([Cl:32])[CH:21]=1)([CH2:18][CH3:19])[CH3:17].[SH:33][C:34]1[S:35][CH2:36][CH2:37][N:38]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:16]([C:20]1[C:25]([O:26][CH2:27][C:28]([N:38]2[CH2:37][CH2:36][S:35][C:34]2=[S:33])=[O:30])=[C:24]([Cl:31])[CH:23]=[C:22]([Cl:32])[CH:21]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: SC1=NCCS1
Reactant: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
A solution of 8.09 g of dicyclohexylcarbodiimide and 340 mg of 4-dimethylamino-pyridine in 60 ml of methylene chloride was added at -5°/0° C. to a solution of 9.78 g of (6-sec-butyl-2,4-dichloro phenoxy) acetic acid and 4.63 g of 2-mercaptothiazoline in 80 ml of methylene chloride and the mixture was stirred for 10 minutes at 0° C. and for four hours at ambient temperature. After filtering off the insolubles, the filtrate was evaporated to dryness, and the residue was chromatographed on silica (eluant: hexane-ethyl (7-3)) to obtain 10.3 g of expected product melting at 96° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1)#[CH:16]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: CNc1ccc(I)cn1
Product: C#Cc1ccc(NC)nc1

Procedure:
(5-Ethynyl-pyridin-2-yl)-methyl-amine was prepared from (5-iodo-pyridin-2-yl)-methyl-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([O:21][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1cc(Cl)ccc1OC[C@H](O)CN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(Cl)ccc1OC[C@@H](CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a reaction vessel were added crude (R)-1-(4-chloro-2-acetoxyphenoxy)-3-phthalimido-2-propanol 364 mg (0.90 mmol), triethylamine 137 mg (1.36 mmol) and ethyl acetate 2 mL. To this mixture was slowly dropped methanesulfonyl chloride 134 mg (1.18 mmol) in an ice bath and then the mixture was stirred at room temperature for 3 hours. After washing with an aqueous 5% HCl solution and water successively, the organic layer was taken and the solvent was evaporated to give crude (R)-1-(4-chloro-2-acetoxyphenoxy)-2-methanesulfonyloxy-3-phthalimidopropane 213 mg (yield 98%, chemical purity 97%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:28]3[CH:29]=[C:24]([CH2:23][NH:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:25]=[CH:26][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 3-((methylsulfonylamino)methyl)phenylboronic acid via General Procedure A to give crude (3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)phenyl)-N-methylsulfonylmethanamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 126 after purification by reverse HPLC. MS (Q1) 499 (M+)