Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6]([C:8]([O:10]C)=O)=[CH:5][CH2:4][N:3]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].Br[CH2:19][Cl:20].C([Li])CCC.P([O-])([O-])([O-])=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[Cl:20][CH2:19][C:8]([C:6]1[CH2:7][C@@H:2]([CH3:1])[N:3]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:4][CH:5]=1)=[O:10]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)C[C@H]1C
Reactant: ClCBr
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC=C(C(=O)CCl)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1-allyl 4-methyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (0.30 g, 1.25 mmol) and bromochloromethane (125 μl) in THF (15 ml) was added −90 to −80° C. a solution of n-butyllithium in hexane (1.59M, 1.15 ml) over a 15 minutes period. After stirring for additional 15 minutes, the reaction mixture was poured into a mixture of-ice (10 g) and phosphate buffer (pH 7.0, 10 ml). After ethyl acetate was added thereto and the mixture was separated by a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give allyl (2R)-4-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (255 mg, 80%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].[CH2:13](N(C(C)C)C(C)C)[CH3:14].BrCC>C(Cl)Cl>[CH2:13]([N:8]1[CH2:7][C:6]2[CH:1]=[C:2]([NH2:12])[CH:3]=[CH:4][C:5]=2[S:11][CH2:10][CH2:9]1)[CH3:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc2c(c1)CNCCS2
Solvent: CCBr
Solvent: ClCCl
Product: CCN1CCSc2ccc(N)cc2C1
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00039 mol) and N-ethyldiisopropylamine (0.066 g, 0.00047 mol) in DCM (4 mL) was added bromoethane (0.051 g, 0.00047 mol), stirred 20 h and evaporated to give 8-ethyl-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g) as an oil. MS (ESI+): 209 (M+H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]2([C:34]([F:37])([F:36])[F:35])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Mn]([O-])(=O)(=O)=[O:41].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C:13]2([C:34]([F:35])([F:36])[F:37])[CH2:14][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:20][CH:19]=3)[C:16](=[O:41])[CH2:17]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(N2CC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)CC2=O)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 75 h
Yield: 26 %

Procedure:
N-{[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoro-methyl)pyridin-3-yl]methyl}propanamide (0.3 g), benzyltriethylammonium chloride (0.35 g) and potassium permanganate (0.25 g) were added to dichloromethane (20 ml), and the mixture was stirred for 75 hours at room temperature. Upon the completion of the stirring, the reaction mixture was filtered through a short silica gel layer to remove precipitate. The filtrate was distilled off under reduced pressure and the purification was carried out by silica gel column chromatography to obtain N-{[6-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methyl}propanamide (0.08 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:34])=[O:33]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-4-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to yield 353 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.21 min; MS: 520.7.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.24 (s, 3H), 6.72 (bs, 1H), 6.88 (d, 1H), 7.03 (t, 1H), 7.16 (t, 1H), 7.30 (d, 1H), 7.52 (t, 1H), 7.51 (t, 1H), 7.64 (s, 1H), 7.67-7.88 (m, 5H), 7.92 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[C:3]=1[CH3:17].S(OC)(O[CH3:22])(=O)=O>>[CH3:22][O:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: CCCCCCCCC1(C)SC(=O)C(C)=C1O
Reactant: COS(=O)(=O)OC
Product: CCCCCCCCC1(C)SC(=O)C(C)=C1OC
Yield: 69.3 %

Procedure:
From 34 (40 mg, 0.16 mmol), KH (27 mg, 0.20 mmol, 30% in mineral oil) and dimethyl sulfate (30 μL, 0.31 mmol) following general procedure H was obtained 37 (30 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=7 Hz, 3H), 1.06-1.09 (m, 1H), 1.24 (s, 10H), 1.41-1.48 (m, 1H), 1.55 (s, 3H), 1.71-1.79 (m, 2H), 1.98 (s, 3H), 4.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 9.59, 14.1, 22.6, 25.2, 26.5, 29.2, 29.4, 29.6, 31.8, 38.9, 58.7, 59.8, 111.3, 180.2, 195.7. IR (NaCl) 2927, 1676, 1631, 1582 cm−1. Analysis Calculated for C15H26O2S: C, 66.6; H, 9.69; Found: C, 66.5; H, 9.67.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[CH3:41][C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][N:43]=1>CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:19]([NH:48][C:46]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:41])[CH:47]=2)=[O:21])=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: Cc1cc(N)ccn1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)Nc3ccnc(C)c3)n2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 29.6 %

Procedure:
A solution of 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (79.87 mg, 0.255 mmol), CDI (82.92 mg, 0.511 mmoles), triethylamine (107 uL, 0.767 mmoles), and DMAP (1.56 mg, 0.012 mmol) was treated with 2-methylpyridin-4-amine (55.30 mg, 0.511 mmol). The reaction was allowed to stir at 100° C. for 16 hours, filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (30.4 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) d 11.10 (s, 1H), 8.69-8.67 (m, 2H), 8.25-8.22 (m, 2H), 7.72 (s, 2H), 6.77 (d, J=3.3 Hz, 1H), 3.99 (d, J=2.9 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.16 (q, J=7.4 Hz, 2H), 2.79 (s, 2H), 2.68 (s, 3H) and 1.25 (t, J=7.3 Hz, 3H) ppm; MS (ES+) 403.0
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24].C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:32]([O:27][C@@H:22]([C:3]1[C:4]([CH3:21])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:23]([O:25][CH3:26])=[O:24])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reaction time: 2.5 h
Yield: 72.3 %

Procedure:
To a stirred solution of (S)-methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (888 mg, 2.301 mmol) in CH2Cl2 (45 mL) and t-butyl acetate (21.76 mL, 161 mmol) at rt was added 70% perchloric acid (0.593 mL, 6.90 mmol). After 2.5 h, the reaction mixture was diluted with CH2Cl2 (50 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatography on silica gel column using (10-40% EtOAc/Hex as eluant) to afford the desired (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (735 mg, 1.663 mmol, 72.3% yield) as white solid. 150 mg of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ 7.76-7.70 (m, 2H), 7.18 (d, J=7.9 Hz, 1H), 6.91 (s, 1H), 5.68 (s, 1H), 3.76 (s, 3H), 2.89-2.84 (m, 4H), 2.68 (s, 3H), 1.89-1.83 (m, 4H), 1.30 (s, 9H). LCMS (M+H)=444.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13]1([S:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:13]1([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(CN2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of 11.5 g. (50 mmole) methyl 4-bromomethylbenzoate, 11.3 g. (50 mmole) 1-benzenesulphonylpiperazine, 6.91 g. (50 mmole) powdered potassium carbonate and 100 ml. butan-2-one is maintained at reflux temperature for 20 hours, then suction filtered while hot and the filtrate evaporated. After cooling, the product is filtered off with suction and recrystallised from methanol to give 11.6 g. (62% of theory) of the desired product; m.p. 145°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[S:18][C:17]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=4)[CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:16]=3[C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:9]=1)[CH3:2].[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1.CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu]I>[CH2:1]([O:3][C:4]1[C:5]2[S:18][C:17]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([N:34]5[CH:38]=[CH:37][CH:36]=[N:35]5)=[CH:29][CH:28]=4)[CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:16]=3[C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:9]=1)[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(I)cc3)cc(C(F)(F)F)c12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(-n4cccn4)cc3)cc(C(F)(F)F)c12

Procedure:
0.30 g (0.5 mmol) 4-ethoxy-9-trifluoromethyl-7-(4-iodo-phenyl)-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine, 0.14 g (2.1 mmol) pyrazole, 0.22 g (1.0 mmol) potassiumphosphate-tribasic, 0.06 g (0.3 mmol) copper(I)-iodide and 0.014 g (0.1 mmol) (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine in 5 ml N,N-dimethylformamide (dry) are stirred at 110° C. under nitrogen atmosphere for 24 h. The solvent is removed in vacuo and the residue is suspended in 20 ml water, sucked off, washed with 100 ml water and suck dried. Following purification by means of flash chromatography (methanol/dichloromethane 1:10) 0.04 g (15%) 4-ethoxy-9-trifluoromethyl-2-piperazin-1-yl-7-(4-(1H-pyrazol-1-yl)-phenyl)-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine is obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1
Reactant: NC(CO)Cc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC(CO)Cc3c[nH]c4ccccc34)cc2c1=O
Yield: 33 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-3-(1H-indol-3-yl)-propan-1-ol according to the GPA affording 18.8 mg (33%) of a red powder. Rt=4.27 min.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:17])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2occc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2occc21
Reaction time: 48 h
Yield: 37.7 %

Procedure:
To a solution of 6,7-dihydro-1-benzofuran-4(5H)-one (2.0 g) in methanol (50 ml) was added 3 Å sieves (15 g), ammonium acetate (11.3 g) and sodium cyanoborohydride (1.22 g). After 48 h of stirring, the reaction mixture was filtered through celite, concentrated, dissolved in 1 N HCl (100 ml) and washed with ethyl ether (3×100 ml). The Aqueous layer was basified to pH 10 (NaOH), extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated to yield (760 mg, 38%) of the title compound as an oil:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[Ca+2].[Cl-].Cl>C(OCC)(=O)C.O>[OH:27][C:21]1[CH:26]=[CH:25][C:24]([C:17]2([C:24]3[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=3)[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]3)[CH2:15][CH2:16]2)=[CH:23][CH:22]=1
Reactant: Oc1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCC2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
4-[2-(Trans-4-n-pentylcyclohexyl)ethyl]cyclohexanone (112.4 g), phenol (152.7 g) and calcium chloride (90.1 g) were mixed, followed by gradually dropwise adding conc. hydrochloric acid (68 ml) with vigorous stirring at room temperature, agitating the mixture for 30 minutes after completion of the dropwise addition, further allowing the resulting material to stand at room temperature for 24 hours, adding hot water (0.5 l) and ethyl acetate (2 l) to dissolve it on heating, washing with saturated NaCl aqueous solution using hot water at 40° to 50° C., drying over Na2SO4, filtering, concentrating and recrystallizing the resulting concentrate from a mixed solvent of ethyl alcohol and methyl alcohol (87:13) (SOLMIX® made by Nihon Kasei Co., Ltd.) to obtain white crystals of 1,1-bis(4-hydroxyphenyl)-4-[2-(trans-4-n-pentylcyclohexyl)ethyl]cyclohexane (78.8 g) as a diol compound of the present invention. M.P.: 203.4-204.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(I)ccc1Cl
Temperature: 50 °C

Procedure:
To 1-chloro-4-iodo-2-nitrobenzene (1.27 g, 4.49 mmol) in methanol (20 ml) was added iron powder (1.25 g, 22 mmol) and the reaction heated to 50° C. A solution of ammonium chloride (1.92 g, 36 mmol) in water (10 ml) was added slowly and the reaction heated to 70° C. overnight. Reaction was cooled, filtered through celite, washed with methanol and solvent reduced in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to 10% ethyl acetate in hexane) to afford the title compound. MS (ES+) m/e 254 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 116 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140 mg, 0.32 mmol), N-(4-aminophenyl)-N-methylacetamide (63 mg, 0.38 mmol) and trimethylsilyl chloride (TMSCl) (0.080 mL, 0.63 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. overnight. More N-(4-aminophenyl)-N-methylacetamide (63 mg, 0.38 mmol) was then added. The mixture was then stirred at 116° C. for an additional 24 h. It was then purified by HPLC to give N-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide as a solid (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:11]2=[O:27])=[CH:7][CH:6]=1)=[O:4].[H][H]>[Pt].C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:12]2[CH2:13][CH2:14][CH2:15][C:10](=[CH:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:29][CH:28]=3)[C:11]2=[O:27])=[CH:22][CH:21]=1)=[O:24].[CH3:26][O:25][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:12]2[CH2:13][CH2:14][CH2:15][C:10](=[CH:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:29][CH:28]=3)[CH:11]2[OH:27])=[CH:22][CH:21]=1)=[O:24]
Reactant: [H][H]
Agent: [Pt]
Agent: COC(=O)c1ccc(C=C2CCCC(=Cc3ccc(C(=O)OC)cc3)C2=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=C2CCCC(=Cc3ccc(C(=O)OC)cc3)C2O)cc1
Temperature: 175 °C
Reaction time: 6 h

Procedure:
An autoclave containing 2,6-bis(4'-methoxycarbonylbenzylidene)cyclohexanone (5.0 g, 0.0128 mol), 5% platinum on carbon (0.5 g) and toluene (100 mL) is pressurized to 50 psig with hydrogen, heated to 175° C. and then pressurized with hydrogen to a total pressure of 250 psig. The autoclave is maintained at 175° C. and 250 psig for 6 hours and then cooled and vented. The contents of the autoclave are transferred to a round bottom flask and the solvent removed. The residue is dissolved in a minimum of methylene chloride and the products separated using medium pressure liquid chromatography to yield 2.73 g (0.0069 mol) of 2,6-bis(4'-methoxycarbonylbenzylidene)cyclohexanone and 1.03 g (0.0026 mol) of 2,6-bis(4'-methoxycarbonylbenzylidene)cyclohexanol. Both the ketone product [FDMS: M+/e=394; IR (CH2Cl2): 1273, 1690, 1720 cm(-1)] and the alkanol product [FDMS: M+/e=396; IR (CH2Cl2 ): 1284, 1720, 3500 (br) cm(-1)] are obtained as a mixture of the cis and trans cyclohexanol isomers which are identified on the basis of their infrared and mass spectra.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:35]1[CH:34]=[C:33]([CH3:37])[N:32]=[CH:31][C:30]=1[C:26]1[CH:25]=[C:24]([C:22]2[CH2:21][C:20](=[O:38])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M225) (312 mg, 0.576 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][C:16]([O:18]C)=[O:17].C(=O)([O-])[O-].[Na+].[Na+].CO>O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(OC)c(CC(=O)O)ccc2c1
Reaction time: 24 h

Procedure:
A mixture of 25 g. of methyl 1,6-dimethoxy-2-naphthylacetate, 15 g. of sodium carbonate, 200 ml. of methanol, and 25 ml. of water are allowed to stand for 24 hours. The reaction mixture is then acidified with 200 ml. of 2N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate, and evaporated to yield 1,6-dimethoxy-2-naphthylacetic acid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][NH2:11])[N:5]=[CH:4]1.C(N(CC)CC)C.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([NH:26][C:27]([NH:11][CH2:10][CH2:9][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCc1c[nH]cn1)NCc1ccccc1
Reaction time: 1 h

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propanamine dihydrochloride and 10 mmol of triethylamine are mixed in 10 ml of acetonitrile and, after addition of 5 mmol of benzyl isocyanate, the whole mixture is brought to boiling for 1 h at reflux. After evaporation under vacuum, the title compound is taken up in a small amount of water and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.