Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)([CH3:21])[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19]([CH3:21])([CH3:20])[CH2:22][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:7][O:6]2)=[CH:16][CH:17]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 85.1 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 81.5 g (0.2655 mol) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C. in the course of about 2 hours. 28.7 g (0.53 mol) of sodium methylate are added at the same temperature. The entire reaction mixture is subsequently stirred for 12 hours and is then concentrated in vacuo. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 72.6 g (85.2% of theory) of crude 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane are obtained and are further reacted directly. ##STR156##
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OC(C)(C)C)=O>C(#N)C>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1(Cc2ccccc2)CNCCNC1
Temperature: 60 °C
Yield: 139.9 %

Procedure:
In a 50 ml round-bottom flask the amine 5 (1.65 g 4.7 mmol) was dissolved in acetonitrile (15 ml) and K2CO3 (5.16 g, 37 mmol) was added. t-Butyl bromoacetate (4.55 g, 23.4 mmol) was slowly dropped into the stirred heterogeneous mixture, while maintaining the temperature <10° C. (ice bath). After the addition the mixture was heated at 60° C. with stirring until TLC showed complete conversion. The precipitate was filtered and washed with dichloromethane; the filtrate and the washings were combined and evaporated in vacuo to give the crude product. The semisolid residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 9.3/0.7), obtaining pure 6 as pale yellow oil (1.35 g, 36%). ESI-MS: 832 (MNa+), 810 (MH+); (Calc. for C46H87N3O8: 809 u.m.a.).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([Cl:17])[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:8]=1
Reactant: CC(C)Oc1ncc(-c2nc(Br)ns2)cc1Cl
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Yield: 123.6 %

Procedure:
5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-chloro-2-[(1-methylethyl)oxy]pyridine (D109) (1.3 g, 3.89 mmol), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.239 g, 7.77 mmol), tripotassium phosphate (2.474 g, 11.66 mmol) and Pd(Ph3P)4 (0.449 g, 0.389 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (5.00 mL) were heated by Biotage Initiator to 120° C. for 30 min. The reaction solution was concentrated and the slurry was diluted with ethyl acetate, washed with water, dried and purified by ISCO column chromatography to afford 3-chloro-5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]pyridine (D110) (2 g). MS (ES): C21H22ClN3O2S requires 415.1. found 416.1 (M+H+).
Reaction SMILES: C(N[C:14](=[O:29])[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([CH3:27])[C:17]=1[CH3:28])CCCCCCCCCCC.[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH3:30][N:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:14](=[O:29])[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]([OH:26])=[C:18]([CH3:27])[C:17]=1[CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: CCCCCCCCCCCCNC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
N-n-dodecyl-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)acetamide is made by an analogous procedure by substituting n-dodecylamine for N-methyl-N-n-octadecylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:20]Br.O>CC(O)=O>[Br:20][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nc(Br)cnc1N1CCNCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a mixture of 2-chloro-3-(1-piperazinyl)pyrazine (5.94 g, 30 mmol, from Example 90, Step 1) and Na2CO3 (6.0 g, 57 mmol) in AcOH (25 mL) was added a solution of Br2 (6.00 g, 38.0 mmol) in AcOH (25 mL) dropwise at room temperature. The reaction mixture was stirred overnight. Water (50 mL) was added and the solution was stirred for 30 min and then concentrated to a small volume. Water (20 mL) was added and the solution was basified to pH 9 by adding solid Na2CO3. The mixture was extracted with CH2Cl2 containing 10% MeOH. The combined extract was evaporated to dryness and the residue was recrystallized from MeOH to give 7.43 g (89%) of the title compound: mp 114-115° C. HRMS m/z calcd for C8H10BrClN4 (M)+ 275.9777, found 275.9765.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[C:9]1(=[O:11])[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6](=[O:12])[CH2:7][CH2:8]1
Reactant: O=C1CCC(=O)N1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN1C(=O)CCC1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
Dimethylformamide (800 ml) was added to a mixture of succinimide (248 g, 2.5 mol), potassium carbonate (346 g, 2.5 mol) and ethyl 5-bromopentanoate (400 g, 1.9 mol). The mixture was heated at 110°-120° C. for 3 h before being cooled to RT. Water (2.5 L) was added and the mixture was extracted with methyl tert-butylether (4×1 L). The combined extracts were washed with water (400 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound (310 g, 71%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (37 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 213. MS m/z 404.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 11.11 (s, 1H), 9.22 (dd, 1H), 9.13 (dd, 1H), 8.55 (dd, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.83-7.78 (m, 1H), 7.71-7.65 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.35 (m, 3H), 3.90 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous potassium carbonate (20.36 g, 146 mmol) and a catalytic amount of potassium iodide were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with 3×100 mls of ethyl acetate. The combined organics were washed with 5% KOH (2×100 mls), brine solution and then dried over magnesium sulfate. The concentrated product was then recrystallized from a 1:1 mixture of ethyl acetate/hexane to give 14 g of an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](O)([C:15]3[C:23](O)=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1.O1C2C=CC(C3(O)C4C(=CC=CC=4)N(CCCCC)C3=O)=CC=2OC1>>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([CH:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]([CH2:5][CH2:4][CH2:1][CH2:2][CH3:3])[C:7]3=[O:26])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (90%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.14 (d, 1H), 7.03 (td, 1H), 6.89 (d, 1H), 6.75 (d, 1H), 6.67 (dd, 1H), 6.57 (d, 1H), 5.90 (s, 2H), 4.50 (s, 1H), 3.81-3.62 (m, 2H), 1.76-1.62 (m, 2H), 1.41-1.28 (m, 4H), 0.88 (t, 3H); 13C NMR (75 MHz, CDCl3) 6176.8, 148.1, 147.2, 143.5, 130.0, 129.4, 128.4, 125.1, 122.9, 122.0, 108.7, 108.6, 101.1, 51.9, 40.4, 29.0, 27.1, 22.3, 14.0.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>C(Cl)Cl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:16][CH:15]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 79.9 %

Procedure:
To a suspension of Intermediate 12b (1 g, 3.87 mmol) in DCM (20 ml) was added COMU (1.891 g, 4.26 mmol) and DIPEA (0.812 ml, 4.65 mmol). The yellow solution was stirred for 2 min at rt and turned red. 2-Dimethylaminoethylamine (0.518 ml, 4.65 mmol) was added and the reaction mixture was stirred at reflux for 1 hr. After cooling to rt, the mixture was washed with water, saturated aqueous NH4Cl and extrated with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (ISCO CombiFlash Rf, 120 g silicagel; A=dichloromethane, B=DCM:7N NH3 in MeOH (9:1), 2% hold for 5 min, gradient to 50% B over 15 min). Fractions containing the product where combined to yield 1.355 g. The final product (1.015 g) was obtained after crystallisation from heptane as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1>O.[Pd].CO>[C:17]1([CH2:16][C:10]2([CH2:13][CH2:14][OH:15])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: OCCC1(Cc2ccccc2)CCNC1
Reaction time: 24 h

Procedure:
Combine 1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (0.72 g, 2.45 mmol) and methanol (20 mL). Add 20% palladium hydroxide-on-carbon (0.231 g). Hydrogenate in a Parr apparatus at an initial pressure of 50 psi. After 24 hours, filter through celite, rinse with methanol. Evaporate the filtrate in vacuo to give the title compound: Rf=0.01 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Cl:13])=[CH:11][NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14](N1C=CN=C1)(=[O:16])[CH3:15]>CCOCC.O>[C:14]([N:10]1[CH:11]=[C:12]([Cl:13])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9]1)(=[O:16])[CH3:15]
Reactant: Clc1cccc(-c2c[nH]cc2Cl)c1
Reactant: CC(=O)n1ccnc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)n1cc(Cl)c(-c2cccc(Cl)c2)c1
Yield: 57.8 %

Procedure:
The mixture of 6.5 g of 3-(3-chlorophenyl)-4-chloropyrol and 10.1 g of N-acetylimidazole was heated for one hour at 100°-110° C. After cooling, the reaction mixture was dissolved in a mixture of 200 ml of ether and 20 ml of water and the resulting ether solution was treated as in Example 4 to obtain 4.5 g of the desired product (colorless crystal, m.p. 88°-90° C.).
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CON(C)C(=O)[C@]1(C)COC(C)(C)O1

Procedure:
The compound prepared in Example 130(a) (12.4 g), acetone (150 mL), acetone dimethylacetal (18 mL) and p-toluenesulfonic acid monohydrate (290 mg) were stirred at room temperature for an hour. The reaction mixture was concentrated, poured into a cold aqueous solution of sodium hydrogen carbonate and extracted with a mixed solution of ethyl acetate-hexane (1:1). The obtained organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuum condition and dried to give the title compound (8.4 g) having the following physical data.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(=S)=S.O>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Aluminum chloride (9.3 g) was added in a single portion to a mixture of 4-nitrobenzoyl chloride (10 g) and toluene (6.3 mL) dissolved in carbon disulfide (35 mL). The mixture was warmed from room temperature to reflux and heated for 3 hours. Concentrated hydrochloric acid (19 mL) was slowly added, and the mixture stirred for an additional 30 minutes, poured into water, and extracted with dichloromethane (3×). The extract was washed with dilute ammonium hydroxide and water, dried (Na2SO4), and evaporated. Recrystallization from ethyl acetate gave 4-(4-methylbenzoyl)-nitrobenzene (10.6 g, 82%) as a pale yellow solid, m.p. 122.4-123.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C.C([O-])(O)=O.[Na+]>[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:15]2[C:14]([F:24])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:8]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:9]=3)[N:16]=2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(Cc5ncc[nH]5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.16 g, 0.32 mmol) in 1,2-dichloroethane (2 mL) was added 1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops of acetic acid and Na(OAc)3BH (0.10 g, 0.49 mmol). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled to room temperature and diluted with aqueous saturated NaHCO3 solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH/CH2Cl2) to afford the product, 4a.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(I)cc1
Yield: 45 %

Procedure:
A mixture of 4.36 g (20.0 mmol) of p-iodotoluene (purchased from Tokyo Kasei), 3.9 g (22 mmol) of N-bromosuccinimide (purchased from Tokyo Kasei) and 60 ml of carbon tetrachloride (purchased from Wako Junyaku Kogyo) was refluxed under the irradiation by means of an incandescent lamp for 4 hours to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide (as a white crystalline). Subsequently, to 0.49 g (10 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 10 ml of dimethyl sulfoxide (purchased from Aldrich) solution heated at 50° C. was added 1.48 g (5.00 mmol) of the above 4-iodobenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 0.84 g (yield: 68.9%) of 4-iodophenylacetonitrile as a white crystalline.
Reaction SMILES: [N+:1]1([O-:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Si]([C:13]#[N:14])(C)(C)C.CN(C)C(Cl)=O.O>C(Cl)Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N+:1]=1[O-:8])#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc[n+]([O-])c(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-picoline-N-oxide (20 g) in CH2Cl2 (360 mL) was added TMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride (16.6 mL) was added slowly dropwise. The mixture was stirred at RT overnight, poured onto 400 mL H2O, and 40 g NaCO3. Separation of layers and evaporation of CH2Cl2 gave 17.25 g of 2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p. 95°-98° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([Cl:38])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:38][C:22]1[CH:21]=[C:20]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: Fc1ccc2c(c1)CNCC2
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3ccc(F)cc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (151 mg, 1.35 mmol), 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (122 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[CH:5]2.[NH2:14][C@@H:15]([CH3:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([NH2:14])[CH3:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1ncc2cc(I)ccc21
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of 5-iodo-1-isopropyl-1H-indazole (129c, 461 mg, 1.26 mmol), (1R,2S)-2-amino-1-phenylpropan-1-ol (286 mg, 1.89 mmol), copper (I) iodide (25 mg, 130 μmol), and cesium carbonate (1.45 g, 3.8 mmol) in butyronitrile (5 ml) was stirred at 125° C. for 2 h. Then the mixture was cooled to r.t., the inorganic material was removed by filtration and washed with ethyl acetete. The combined organic solutions were concentrated in vacuo, and the product purified by flash chromatography on silica gel (ethyl acetate/methanol). Yield 200 mg (51%) of a brown oil.