Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([Cl:18])=[N:7][C:6]=2[CH:16]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Br)ccc2Oc2cscc21
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Br)ccc2Oc2cscc21

Procedure:
A 2.13 g. portion of 7-bromo-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 9) and 1.5 g. of phosphorus pentachloride in 40 ml. of dry toluene are reacted as described in Example 9, giving 7-bromo-10-chloro-thieno[3,4-b][1,5]benzoxazepine which is further reacted with N-methylpiperazine in 15 ml. of dry toluene giving the base compound as a foam which is then converted to the hemifumarate, m.p. 196°-197° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1cccs1
Yield: 58.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.79 g, 59%) as white crystals (mp 45-46° C.). IR: 3400-2500, 1720, 710 cm-1 ; 1H-NMR: 1.45 (m, 8 H), 2.35 (m, 4 H), 5.55 (m, 1 H), 6.50 (d, 1 H), 7.00 (m, 3 H), 11.00 (bs, 1 H). Anal. Calcd. for C13Hl8SO2 : C, 65.51, H, 7.61%; Found: C, 65.58, H, 7.63%. Z:E=75:25.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:42]=[CH:41][C:8]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH:20]=[C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[NH:23][C:22]4=[O:32])=[CH:17][CH:18]=3)[N:13](COCC[Si](C)(C)C)[N:12]=2)=[CH:7][CH:6]=1)[CH3:3].B(F)(F)F.CCOCC.Cl>>[CH3:1][N:2]([CH2:4][C:5]1[CH:42]=[CH:41][C:8]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH:20]=[C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[NH:23][C:22]4=[O:32])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(C=Cc4ccc(CN(C)C)cc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=Cc1ccc3c(C=Cc4ccc(CN(C)C)cc4)n[nH]c3c1)C(=O)N2

Procedure:
According to the method of Example A22B, 3-((3-(4-((dimethylamino)methyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (19 mg, 0.033 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl (water/EtOH) treatment. The solvents were removed in vacuo using additional EtOH to azeotropically remove water. The residue was dissolved in MeOH/EtOAc and filtered to remove solid, then the solvent was evaporated in vacuo. Purification by prep-HPLC gave the title compound (E isomer, first eluting fraction, 94% by HPLC) as an orange solid (11 mg, 60%. 1H NMR (400 MHz, CD3OD) 8 ppm 8.26 (d, J=8.5 Hz, 1H), 7.88 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 7.61 (s, 2H), 7.51-7.58 (m, 3H), 7.26 (s, 1H), 6.84 (s, 2H), 4.34 (s, 2H), 3.63 (s, 3H), 2.89 (s, 6H); MS ESI 451.2 [M+H]+, calcd for [C28H26N4O2+H]+ 451.22. The second eluting fraction was the Z-isomer (5 mg, 30%). 1H NMR (400 MHz, CD3OD) δppm 8.89 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.99 (dd, J=9.0, 1.3 Hz, 1H), 7.90 (s, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.57-7.61 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.33 (d, J=2.0 Hz, 1H), 6.85 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.34 (s, 2H), 3.84 (s, 3H), 2.89 (s, 6H); MS ESI 451.2 [M+H]+, calcd for [C28H26N4O2+H]+ 451.22.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH2:12]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)[C:11]#[CH:10]
Reactant: O=Cc1cc[nH]c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1ccc(C=O)c1
Reaction time: 0.17 h

Procedure:
2.924 g of pyrrole-3-carboxaldehyde (J. Org. Chem. 1981, Vol. 46, p. 839) dissolved in 45 ml of tetrahydrofuran and 1.488 g of sodium hydride as 50% in oil were admixed and then were stirred for 10 minutes cold, then for 40 minutes at room temperature. After cooling, 2.5 ml of propargyl bromide were added with stirring at 5 C. for 90 minutes. A further 2 ml of propargyl bromide were added with stirring at 5° C. for 1 hour and the mixture was poured into water and extracted with methylene chloride. The solvent was distilled off at atmospheric pressure to obtain 2.868 g of 1-(2-propynyl)-1H-pyrrole-3-carboxaldehyde which was purified by chromatography on silica gel and elution with a 65-35 hexane-ethyl acetate mixture to obtain 2.868 g of the said product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:20]C=2C=1.[NH4+].[OH-]>CC#N>[CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([NH2:20])=[O:6])[CH3:2]
Reactant: CCOC(C)(C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCCl
Product: CCOC(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of 2-ethoxy-2-methylpropanoic acid (1.1 g, 8.32 mmol) in MeCN (15 mL) was treated with EDC (1.596 g, 8.32 mmol) and HOBT (1.275 g, 8.32 mmol), stirred at RT for 2 h, treated with NH4OH (˜15M, 1.7 mL, ˜25.5 mmol) and stirred at RT overnight. The mixture was treated with satd. NaHCO3 and water, extracted with EtOAc (5×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 2-ethoxy-2-methylpropanamide (1.1 g, 101%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.03 (s, 2H), 3.31 (q, J=7.0 Hz, 2H), 1.21 (s, 6H), 1.10 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20](CC3C=CC=CC=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:34]([O:41][C:42](Cl)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a refluxing solution of 4.3 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 50 ml of benzene, a solution of 4.55 g of benzyloxycarbonyl chloride in 10 ml of benzene is added dropwise for 15 minutes. The mixture is refluxed for one hour, and said mixture is evaporated under reduced pressure to remove solvent. 30 ml of ethanol and 50 ml of an aqueous sodium hydroxide solution are added to the residue, and the mixture is stirred at room temperature for 2 hours. Then, the mixture is diluted with water, and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and evaporated to remove solvent. 4.79 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:28])[F:27])=[CH:13][CH:12]=1)=[O:10].[C:30](Cl)(=[O:32])[CH3:31].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:30](=[O:32])[CH3:31])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:27])[F:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (70 mg, 0.159 mmol) (intermediate 2) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (0.5 ml) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2.0 h. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution 5% HCl and water. The solid obtained was purified by silica gel column chromatography using 10% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 234° C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N+:10]=1[O-].C(O)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[C:13]([C:12]1[CH:15]=[CH:16][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[N:10][CH:11]=1)#[N:14]
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)OCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (3.2 g, 31.31 mmol) is heated to 115° C. under an argon atmosphere. The compound of Example 30A (700 mg, 5.22 mmol) is added and the solution is stirred at reflux for one hour. Ethanol (3 ml, 51.12 mmol) is added dropwise to the mixture and refluxing is continued for 10 minutes. The mixture is cooled to room temperature, poured into ice water and neutralised with saturated sodium bicarbonate solution. The aqueous phase is extracted with diethyl ether. The organic phase is washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo to afford a black oil. The oil is dissolved in dimethylsulfoxide (8 ml) and purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([F:39])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:10]2[N:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:4]=3)[N:9]=2)=[C:26]([F:39])[CH:25]=1
Reactant: CC1(C)OB(c2ccc(Cl)cc2F)OC1(C)C
Reactant: CSc1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1
Product: Fc1cc(Cl)ccc1-c1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1

Procedure:
A solution of 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine and 2-(4-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled together by the method of Example 2 to give 3-(4-chloro-2-fluorophenyl)-5-[4-fluoro-3-(3-fluoro-pyridin-2-yl)phenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.30-7.35 (2H, m), 7.40-7.46 (2H, m), 7.53-7.61 (1H, m), 8.26 (1H, t, J8.2 Hz), 8.42-8.45 (1H, m), 8.54 (1H, dd, J 2.4, 6.6 Hz), 8.62 (1H, d, J 4.6 Hz), 9.69 (1H, s); m/z (ES+) 399.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[K+].O>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Methyl 5-methoxyvalerate (7.33 g, 50.2 mmol) and KOH (14.4 g, 0.256 mol) were dissolved into a mixture of 50 ml of water and 150 ml of MeOH. The solution was stirred at 0° C. for 2 hrs then MeOH was removed in vacuo. After washed by CHCl3 (50 ml), the aqueous layer was acidified to pH=1 by 2N HCl and extracted by Et2O (2×100 ml). Organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-methoxyvaleric acid (5.27 g, 79.6%) was obtained as a colorless oil.
Reaction SMILES: I[C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[CH:39])[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[C:39][C:2]3[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cn1[Si](C(C)C)(C(C)C)C(C)C
Yield: 56.7 %

Procedure:
A mixture of 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole (1.222 g, 3.0 mmol), 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (0.851 g, 3.15 mmol), Pd(PPh)2C12 (105 mg, 0.15 mmol), cuprous iodide (2 g mg, 0.15 mmol), and triethylamine (0.5 mL) in acetonitrile (50 mL) was heated at reflux for 4 hours. The resulting solution was cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with hexanes:ethyl acetate(2:1). The first major fraction is unchanged starting material (270 mg, 32%); the subsequent major fluorescent fractions were combined and concentrated in vacuo to give methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]1-triisopropylsilylpyrrole-2-carboxylate as a pale yellow solid (935 mg, 57%, mp 163-165° C.): 1H NMR (CDCl3) δ 8.90 (br s, 1H), 8.52 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=1.4 Hz), 7.23 (d, 1H, J=1.4 Hz), 3.79 (s, 3H), 1.75 (sept, 3H, J=7.6 Hz), 1.31 (s, 9H), 1.10(d, 18H, J=7.6 Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.[OH-].[Na+].Cl>C(O)CC>[OH:7][CH2:8][CH2:9][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CBr
Reactant: OCCNCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: O=C(O)CN(CCO)CCO

Procedure:
Methyl bromoacetate (152.98 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles) are added and the mixture is stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid is washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml, 1.3 moles). Upon cooling, N,N-bis-(2-hydroxyethyl)aminoacetic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[OH:16][C:17]([CH3:27])([CH3:26])[CH2:18][NH:19][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[OH:16][C:17]([CH3:27])([CH3:26])[CH2:18][NH:19][C:20]1=[N:21][C:22](=[O:25])[S:23]/[C:24]/1=[CH:1]\[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.70 g) in 2-propanol (30 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (3.00 g), and piperidinium acetate (1.18 g). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.72 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=3[S:11][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=1.Cl.[CH:19]1([NH:22][CH3:23])[CH2:21][CH2:20]1>CO>[CH:19]1([N:22]([C:2]2[C:3]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:4]=3[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=2)[CH3:23])[CH2:21][CH2:20]1
Reactant: COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: CNC1CC1
Agent: Cl
Solvent: CO
Product: COCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring suspension of compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (1.0 g, 0.0037 mol) and cyclopropyl methylamine hydrochloride (1.18 g, 0.111 mol) in methanol (100 ml) was added TEA (3.1 ml, 0.022 mol) at 0-5° C. Reaction mixture was then warmed to room temperature and stirred for about 20 h. After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained was diluted with ice-water solution (200 ml). Aqueous phase was extracted with DCM (2×250 ml). Combined organic layer was washed with brine solution, dried and concentrated on rotary evaporator to get crude material which was purified by prep HPLC to get the desired title compound cyclopropyl-(2-methoxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl-amine(N-cyclopropyl-2-(methoxymethyl)-N-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine) as a yellow solid. Yield: (600 mg, 54.5%); 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.82 (m, 2H), 1.72-1.68 (m, 2H), 0.76 1H NMR (400 MHz, DMSO) δ ppm=4.41 (s, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.97-2.92 (m, −0.70 (m, 2H), 0.40-0.36 (m, 2H); LCMS: [M+H]=304.40; HPLC (purity): 99.61% at 236 nm, 99.45% at 220 nm, 99.32% at 254 nm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:25][CH2:24]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.80 mmol) in 2-propanol (50 mL) was added cis-tert-butyl 4-aminocyclohexylcarbamate (425 mg, 1.98 mmol) followed by triethylamine (200 mg, 1.98 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was suspended in dichloromethane (50 mL), washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 550 mg, 67.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]2[O:24][CH2:25]C(=O)[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([O:33][CH3:34])([O:31][CH3:32])OC.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]2[O:24][CH2:25][C:28]([O:31][CH3:32])([O:33][CH3:34])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC2C(OCc3ccccc3)CN(C(=O)OCc3ccccc3)C12
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)COC2C(OCc3ccccc3)CN(C(=O)OCc3ccccc3)C21
Temperature: 60 °C

Procedure:
Compound 12a (7.6 g) was dissolved dry methanol (100 mL). Trimethyl orthoformate (30 mL) and pTsOH (0.2 g) was added at rt under a nitrogen atmosphere. The mixture was heated at 60° C. for 8 hours. Once the reaction was deemed complete according to TLC, it was cooled to rt and concentrated in vacuo. The crude product was purified by column chromatography over silica gel eluting with ethyl acetate-heptane (1:4) to afford after concentration in vacuo the ketal 12b as a clear oil (5.9 g, 71% over 2 steps); ESI+, m/z: 382 (M+ —OMe).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H](O)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:16][CH2:17][C@H:12]([NH2:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), trans-4-aminocyclohexan-1-ol (1.2 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 24 hours, and as a result, trans-4-aminocyclohexyl benzoate was obtained at a yield of 99%.
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][C:11]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1>C(Cl)Cl>[F:40][C:9]([F:8])([F:41])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:12][C:11]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([F:38])([F:39])[F:37])[CH2:32][CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1
Reactant: CC(C)(C)S(=O)Cl
Reactant: Cn1c(Nc2cc(CN)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 99, step (a) using 2-methylpropane-2-sulfinic chloride (117 mg, 0.83 mmol), 4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (400 mg, 0.79 mmol), TEA (160 mg, 1.58 mmol) and DCM (5 mL).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[Cl:9].C(ON=O)(C)(C)C.[FH:17].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][CH:5]=[C:6]([F:17])[N:7]=1
Reactant: Nc1ccc(Cl)c(Br)n1
Reactant: F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(Cl)c(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-5-chloropyridin-2-amine (1 g, 4.82 mmol) in dichloromethane (10 mL) at 0° C. added tert-butylnitrite (1.145 mL, 9.64 mmol) followed by pyridine hydrofluoride (3 mL, 9.64 mmol) and the mixture was stirred at 0° C. for 30 minutes. The mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered, and concentrated to afford of the title compound. 1H NMR (400 MHz, CDCl3): δ 6.90-6.93 (m, 1H), 7.80-7.84 (m, 1H).