Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][C:3]=1C=O.[OH-:15].[Na+].OO>O>[CH3:14][O:13][CH2:12][O:11][C:8]1[C:9]([CH3:10])=[C:2]([OH:1])[C:3]([OH:15])=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C=O)c(O)c1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(O)c(O)c1C
Temperature: 42.5 °C
Yield: 95.9 %

Procedure:
Into a 2.0 L, 4-Necked, RB flask equipped with two addition funnels, thermometer socket and a pH meter was charged 800 mL of DM water. The contents were kept under nitrogen atmosphere. 2-Hydroxy-4-(methoxymethoxy)-3-methylbenzaldehyde (100 g) was added to the reaction mass under stirring. Aqueous sodium hydroxide (0.5 mL, dissolve 24.6 g of sodium hydroxide in 82.0 mL of DM Water) was added to the reaction mass to get a pH of 7.0-8.0. Reaction mass was heated to 40-45° C. Simultaneous addition of aqueous sodium hydroxide and hydrogen peroxide to, the reaction was started using two addition funnels. During the addition pH of the reaction mass was maintained at 7.8-8.4 and the temperature at 40-45° C. After the completion of addition, maintained the reaction mass at 40-45° C. for 4.0 h. The reaction mass was cooled to 25-30° C. and extracted with 3×500 mL of ethyl acetate. Combined organic layer was washed with 500 mL of saturated NaCl solution, treated with 20 g of activated carbon, dried with sodium sulphate, and distilled of solvent under vacuum to get 90 g of crude 4-(methoxymethoxy)-3-methylbenzene-1,2-diol as thick syrup. HPLC purity of sample is about 85%. The material is directly used in next stage. A small sample is purified by column chromatography for characterization purpose. M.R.: 60.5-61.5° C. IR (neat): 3487, 3200, 2969, 2942, 1630, 1621, 1488, 1443, 1405, 1378, 1307, 1290, 1242, 1150, 1086, 1042, 1007, 987, 904, 881, 806, 735, 660, 606 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 8.79 (s, 1H, exchangeable with D2O, OH), 8.19 (s, 1H, exchangeable with D2O, OH), 6.51 (d, J=8.4 Hz, 1H, Ar. H), 6.34 (d, J=8.8 Hz, 1H, Ar. H), 5.02 (s, 2H, OCH2O), 3.36 (s, 3H, OMe), 2.01 (s, 3H, ArCH3). 13C-NMR (CDCl3, 100 MHz): δ 148.45 (C-4), 143.92 (C-2), 139.95 (C-1), 114.64 (C-3), 111.77 (C-6), 105.60 (C-5), 95.16 (OCH2O), 55.49 (OMe), 9.17 (ArCH3). Mass (EI-MS): 184.46 (M), 183.3 (M−1)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][S:38][C:33]1[N:32]=[C:31]([NH2:30])[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:34]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: CSc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1nc(N)cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)n1
Yield: 27.7 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:31])[NH:7][C:8]2[CH:30]=[CH:29][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[S:25][C:24]([C:26]([OH:28])=O)=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41]([NH2:46])([CH2:44][CH3:45])([CH3:43])[CH3:42].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:31])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]4[S:25][C:24]([C:26]([NH:46][C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[O:28])=[CH:23][CH:22]=4)[CH2:18][CH2:19]3)=[O:13])=[CH:29][CH:30]=2)[CH2:3][CH2:2]1
Reactant: CCC(C)(C)N
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(=O)O)s3)CC2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.3 %

Procedure:
5-((4-(4-(3-(Cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)-thiophene-2-carboxylic acid (100 mg, 0.226 mmol), N,N-diisopropylethylamine (99 mg, 0.127 mL, 0.452 mmol) and tert-pentylamine (39 mg, 0.452 mmol) were combined and stirred in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (216 mg, 0.202 mL, 0.339 mmol, 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated under vacuum and purified by reverse phase acidic preparative HPLC to afford the title compound (5 mg). MS (ESI) m/z 512.8 [M+H]+
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CC(=O)OCCOCCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (58 mmol) of 2-(2-methoxyethoxy)ethyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon with 36 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.4 g (58 mmol) of 3,4,5-trimethoxy-benzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: N(OCCC(C)C)=O.[C:9]1([C:15]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][C:22]3[N:21]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[N:20]=[C:19](N)[C:18]=3[CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:41]CI>>[I:41][C:19]1[C:18]2[CH:17]=[CH:16][C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][C:22]=2[N:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:20]=1
Reactant: ICI
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: CC(C)CCON=O
Product: Cc1ccc(S(=O)(=O)n2nc(I)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Temperature: 80 °C

Procedure:
1.21 cm3 of isoamyl nitrite are added to a solution of 1 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-ylamine in 10 cm3 of diiodomethane, and the solution obtained is heated in the region of 80° C. for one hour. The mixture is purified directly by flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (95/5 by volume)], and 0.6 g of 3-iodo-6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.75 (m, 12H) 1.99 (m, 3H) 2.19 (s, 3H) 2.79 (m, 2H) 3.74 (m, 1H) 4.01 (t, J=14.0 Hz, 2H) 4.68 (m, 1H) 7.67 (d, J=8.6 Hz, 1H) 7.72 (d, J=12.4 Hz, 1H) 7.99 (t, J=8.2 Hz, 1H) 8.20 (d, J=7.3 Hz, 1H) 8.23 (s, 1H) 9.08 (s, 1H). [M+H] calc'd for C26H32F3N7O2, 532. found 532.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][OH:13].[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([S:20]([O:23]C)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[C:14]1([CH3:25])[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH3:1][N+:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][OH:13]
Reactant: CN1c2ccccc2CCC1CO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[N+]1(C)c2ccccc2CCC1CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 100 °C
Yield: 202 %

Procedure:
A mixture of 1.3 g of 1-methyl-1,2,3,4-tetrahydro-2-quinolinemethanol and 1.37 g of methyl p-toluenesulfonate was heated at 100° C. for 6 hours. The solvent was removed from the reaction mixture by decantation, and the residue was washed with ether to give 2.7 g of the desired compound as a dark red oil.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23]C(=O)C2C=CC=CC=2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:44]([CH3:46])([CH3:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=2[Se:41]1)(=O)C.[OH-].[Na+].Cl>C1COCC1.CO>[OH:23][C:16]1[CH:17]=[CH:18][C:19]2[C@@H:20]3[C@H:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)[C@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]([CH3:45])([CH3:46])[C:43]4[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=4[Se:41]3)[CH2:13][C:14]=2[CH:15]=1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCN4[Se]c5c([N+](=O)[O-])cccc5C4(C)C)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)c2cccc([N+](=O)[O-])c2[Se]N1CCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 99 %

Procedure:
N-{8-[17β-acetoxy-3-benzoyloxyoestra-1,3,5(10)-trien-7α-yl]octyl}-3,3-dimethyl-7-nitrobenzisoselenazoline (115 mg, 0.15 mmol) is dissolved in 2 ml of THF and 1 ml of methanol. To the obtained mixture is then added an aqueous solution of NaOH (1 ml, 1N, 1.0 mmol). The reaction medium is stirred at room temperature for 22 hours, then neutralized with an aqueous solution of HCl (1N). The mixture is extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous solution of NaCl, dried over MgSO4 and evaporated. The residue is purified by silica gel column chromatography (eluent: EtOAc:cyclohexane, 1:3) to provide the expected product (95 mg, 94%) as a deep red solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([O:15][C:16]([NH:17][N:18]=[C:7]1[CH2:8][CH2:9][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6]1)=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C2CC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN=C1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-cyclopropyl-4-piperidon (10.0 g. 71.8 mmol) and tert-butylcarbazate (9.50 g, 71.8 mmol) in 25 mL THF is stirred for 3 h at RT and then concentrated in vacuo. Yield: 19.2 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][C:9]([CH3:19])([CH3:18])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: C#CC(O)(CCC)CCC
Reactant: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(CC(C)(C)CNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (73) (0.489 g, 1.45 mmol) was coupled with 4-ethynylheptan-4-ol (44) (0.28 g, 2.0 mmol) following the method described in Example 16 and the product was purified by flash chromatography (0 to 50% EtOAc-hexanes gradient) to give 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2,2-dimethylpropyl)acetamide (74) as a yellow oil. Yield (0.350 g, 61%): 1H NMR (400 MHz, CD3OD) δ 7.20-7.25 (m, 3H), 7.12-7.15 (m, 1H), 3.19 (s, 2H), 2.54 (s, 2H), 1.58-1.71 (m, 8H), 0.98 (t, J=7.2 Hz, 6H), 0.85 (s, 6H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])C)[C:17]4[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(CCN)CC[CH2:37][CH2:36]1.[CH3:43]C#N>>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34][CH3:43])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:23][CH2:24][N:25]4[CH2:26][CH2:37][CH2:36][CH2:27]4)[C:17]4[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN(C)C1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Reactant: CC#N
Reactant: NCCN1CCCC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(NCCN1CCCC1)c1ccccc1-3

Procedure:
A 0.03M solution of 5-bromo-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (prepared as in Example 2) in MeCN was treated with (2-pyrrolidin-1-ylethyl)amine (5 eq) at 55° C. for 4 h; evaporation in vacuo to dryness gave crude methyl 13-cyclohexyl-5-[(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Hydrolysis of the foregoing methyl ester was done with IM aqueous KOH (6 eq) in dioxane (0.1M) at 60° C.; the reaction was complete in 2 h, and the title compound was obtained in 24% yield after RP-HPLC purification and lyophilisation (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14]2[C:19]([C:20]3[N:21]=[C:22]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[N:24][CH:25]=3)=[CH:18][N:17]=[C:16](SC)[N:15]=2)[CH2:8]1)(=[O:6])=[O:5].[CH3:40]O.[S:42]([O-:47])(O[O-])(=[O:44])=O.[K+].[K+]>O1CCCC1.O>[CH3:40][S:42]([C:16]1[N:15]=[C:14]([NH:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:7]([S:4]([CH2:3][CH:2]([CH3:39])[CH3:1])(=[O:5])=[O:6])[CH2:8]2)[C:19]([C:20]2[N:21]=[C:22]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])[C:23]3=[N:24][CH:25]=2)=[CH:18][N:17]=1)(=[O:47])=[O:44]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CO
Reactant: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(S(=O)(=O)CC(C)C)C2)n1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine (650 mg, 1.1 mmol) prepared in step 2 of Example 77 above in tetrahydrofuran (5 ml) and methanol (8 ml) was treated with a solution of potassium peroxymonosulfate dissolved in water (4 ml) at 5° C. and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted into dichloromethane (2×). The organic layers were dried (MgSO4) and concentrated in vacuo. Purification was by chromatography (silica gel, 40 g, 5% methanol/dichloromethane) which gave {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine as a foam ˜450 mg. MS (ES+): 623.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][CH2:10][C:11](=[S:13])C.[CH2:14](N(CC)CC)C.O>ClCCl>[Cl:8][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([S:13][CH3:14])=[C:10]([CH3:9])[NH:1][C:2]=12
Reactant: CCC(C)=S
Reactant: Nc1cccnc1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSc1c(C)[nH]c2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.3 %

Procedure:
A solution of 3-amino-2-chloropyridine (1.13 g, 8.84 mmol) in dichloromethane (22.7 ml) was cooled to −78° C. A solution of tert-butyl hyperchloride (2 ml, 17.7 mmol) in dichloromethane (6.8 ml) was added to the solution. The reaction mixture was stirred for 15 minutes and a solution of methylthioacetone (0.91 ml, 8.84 mmol) in dichloromethane (6.8 ml) was slowly added thereto. The reaction mixture was stirred for 90 minutes at the same temperature and a solution of triethylamine (1.36 ml, 8.84 mmol) in dichloromethane (6.8 ml) was added thereto. The reaction mixture was warmed to room temperature and water was added thereto. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 100 mg of the titled compound as a white solid.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH2:18])[C:7]=2[N:8]=[CH:9][N:10]=1>>[NH2:3][C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH2:18])[C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C=C[C@@H](Cn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: C=C[C@@H](Cn1cc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
An 8 N ammonia methanol solution (89.4 ml) was added to the (S)-tert-butyl (1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (20.84 g) obtained in Step 1, and the mixture was stirred in an autoclave at 120° C. for 6 hours. The reaction mixture was cooled with ice, and the solvent was distilled off under reduced pressure. After the resulting residue was diluted with a small amount of methanol, the resulting precipitate was collected by filtration, washed with cold methanol (11 ml), and then dried under reduced pressure to obtain the title compound (8.28 g) as a milky-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].F[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:16]1[CH:19]=[CH:20][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 86.7 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (0.152 g, 1.0 mmol) in dry MeCN (50 mL) was added 4-fluorobenzyl bromide (0.145 mg, 1.0 mmol), and anhydrous K2CO3 (0.27 g, 2.0 mmol). The mixture was refluxed under stirring for 4 h, and then evaporated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc. The separated organic layer was dried with MgSO4, and then evaporated in vacuum. Finally, the residue was eluted through a silica gel column with n-hexane/EtOAc (4:1) to give white compound I (0.21 g, 88%).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.C[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[OH:33].[C:34](=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:7]2[C:2]([O:33][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:27]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:10])=[O:11])=[CH:17][CH:16]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccncc1O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ncccc1Oc1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A 5 mL pear-shaped flask was charged with N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (134 mg, 0.30 mmol), 4-methyl-pyridin-3-ol (100 mg, 0.90 mmol), potassium carbonate (250 mg, 18.0 mmol), and DMA (0.9 mL). The heterogeneous mixture was heated to 150° C. and stirred overnight. The crude reaction mixture was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1 H), 7.95 (d, 1 H), 7.76 (d, 2H), 7.73 (d, 1 H), 7.50 (d, 2H), 7.12 (d, 1 H), 7.04 (dd, 1 H), 2.55 (s, 3H), 1.34 (s, 9H); MS (ES) M+H expect 432.1, found 432.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[OH:13].[Cl:14][CH2:15][CH:16]=O.Cl.O>CC(O)=O>[Cl:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: O=CCCl
Reactant: OCc1ccc(C(F)(F)F)cc1O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)OC(CCl)OC2
Reaction time: 24 h
Yield: 6.1 %

Procedure:
2-(hydroxymethyl)-5-(trifluoromethyl)phenol (1.0 g, 5.2 mmol) was dissolved in AcOH (4 ml) and cooled on ice-bath. Chloroacetaldehyde (0.93 ml, 7.3 mmol) and concentrated HCl (1.0 ml) were consecutively added drop wise. After 24 h, further addition of chloroacetaldehyde (0.50 ml, 3.9 mmol) and concentrated HCl (1.0 ml) were done and the reaction mixture was allowed to stir another 24 h. Water was added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give an oil. Twice purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (0.08 g, 6%). MS m/z (rel. intensity, 70 eV) 252 (M+, 10), 174 (76), 146 (bp), 145 (47), 127 (44).