Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[C:20](F)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CN1C(=O)CCC1.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[C:20]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(Nc1cnccc1Nc1cccc(F)c1F)c1cccnc1F
Reactant: CC(C)(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1ncccc1C(=O)Nc1cnccc1Nc1cccc(F)c1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
To a solution of N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-fluoropyridine-3-carboxamide (4.0 g, 11.6 mmol) in NMP (30 mL) was added t-butylamine (15.0 mL, 145.3 mmol) at RT. The reaction mixture was slowly heated to 100° C. and stirred at this temperature for 48 hr. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (4×100 mL), brine solution (100 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo gave N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-(tert-butylamino)pyridine-3-carboxamide (4.1 g, 89% yield), which was used as is in subsequent reactions; LC-MS: 398.3 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=[C:16]([CH3:38])[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:39][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=[C:16]([CH3:38])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccc2)c1
Yield: 109.9 %

Procedure:
A solution of 3-{2-methyl-4-[3-methyl-5-(2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester (0.137, 0.249 mmol) in ethanol (8 mL) is treated with 5 N NaOH (2 mL) and heated to reflux until saponification is completed. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.143 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O5F3 523.1732, found 523.1721.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O)(C)(C)C.CO[C:26]([CH3:28])=[CH2:27].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+]>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1Cl
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N(C[C@@H]2CCCN2)C(C)C)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-[(4-chloro-3-methoxy-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.68 g, 2.0 mmol) were added 2-methoxypropene (0.216 g, 3.0 mmol), trifluoracetic acid (0.228 g, 2.0 mmol) and sodium triacetoxyborohydride (0.64 g, 3.0 mmol). The mixture was stirred overnight at 60° C. Saturated sodium bicarbonate solution (10 ml) was added and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. Solvent and access trifluoroacetic acid was evaporated, diisopropylethylamine (1 ml) was added to liberate the free base and the mixture was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/heptane 1:1) to yield a light yellow oil, (0.185 g, 33%); MS (ISP): 283.5, 285.2 ((M+H)+.).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:9]([CH3:11])([CH3:10])[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:20])=[CH:18][CH:17]=1)#[N:30]
Reactant: N#CCBr
Reactant: CC(C)(Sc1ccc(O)cc1)C(=O)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(Sc1ccc(OCC#N)cc1)C(=O)NC1CCCCC1
Temperature: 80 °C

Procedure:
N-Cyclohexyl-2-[(4-hydroxyphenyl)thio]-2-methylpropanamide (prepared as example 67) was dissolved in DMF and to this was added potassium carbonate and bromoacetonitrile and the resulting solution was heated to 80° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAC, dried over MgSO4 and concentrated. The product was purified by flash chromatography, eluting with hexane/EtOAc, to provide 19.4 mg of the desired product. LCMS: (M+H)+=333.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:16]([CH2:18][S:19](Cl)(=[O:21])=[O:20])#[N:17].[OH-].[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:19]([CH2:18][C:16]#[N:17])(=[O:21])=[O:20])=[CH:5][CH:4]=1
Reactant: N#CCS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(NS(=O)(=O)CC#N)cc1
Yield: 18.2 %

Procedure:
To a solution of para-anisidine (1.95 g) in acetonitrile (25 ml) at 15° C. under argon atmosphere was added pyridine (1.25 g), then cyanomethanesulfonyl chloride (2 g) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml water and the pH was made basic by addition of 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, then concentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane 1:1) afforded the title product as an orange solid (590 mg). 1HNMR (CDCl3, 400 MHz): 7.30 (d, 2H), 6.95 (d, 2H), 6.70 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]2[C:14]([CH:15]=[C:16]([O:18]C)[CH:17]=1)=[C:13]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[C:12](=[O:28])[CH:11]=[CH:10]2.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]2[C:14]([CH:15]=[C:16]([OH:18])[CH:17]=1)=[C:13]([C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26])[C:12](=[O:28])[CH:11]=[CH:10]2
Reactant: COc1cc(-c2ccccc2Cl)n2ccc(=O)c(-c3c(Cl)cccc3Cl)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1ccn2c(-c3ccccc3Cl)cc(O)cc2c1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 6-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-8-methoxy-2H-quinolizin-2-one (Example 14, 40 mg) in methylene chloride was added boron tribromide (0.06 mL) at −78° C. The mixture was warmed to room temperature and stirred for 12 h. After quenching with 2N HCl, the mixture was extracted with methylene chloride, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel (methylene chloride/methano-=7/1) to give title compound (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:15][CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]1[C:6]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=2)[N:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Temperature: 90 °C

Procedure:
6-(2-Chlorobenzoyl)-5-(2-nitroethenylamino)indan (4.8 g) was added in small portions to a solution of DBU (4.8 g) in benzene (50 ml) with heating at 90° C. The mixture was refluxed for 30 minutes and, then, washed with 2N HCl and water and dried (MgSO4). The solvent was then distilled off to give crystals of 4-(2-chlorophenyl)-7,8-dihydro-3-nitro-6H-cyclopenta[g]quinoline. The crystals were collected by filtration and washed with methanol (4.50 g, 99.1%). Recrystallization from ethanol gave light brown prisms, mp. 175°-176° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:21]=O)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24]O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]#[N:24])=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccc([N+](=O)[O-])cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C#N)c2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Yield: 66.7 %

Procedure:
6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (0.2 g, 0.622 mmol, prepared using N from 6-nitro-1H-indazole-3-carbaldehyde [Chempacific]), hydroxylamine hydrochloride (0.048 g, 0.68 mmol), and TEA (0.095 mL, 0.68 mmol) were combined in DMF (1.24 mL) in a sealed vial. 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (50% solution in DMF, 0.400 mL, 0.684 mmol) was added and the mixture was heated at about 100° C. for about 6 h. The mixture was allowed to cool to rt. EtOAc (15 mL) and an aqueous solution of saturated NaHCO3 (5 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (1×5 mL). The combined extracts were washed with 5% aqueous LiCl (3×10 mL). The combined extracts were washed with brine (10 mL), dried over MgSO4, filtered and evaporated under vacuum. The sample was re-dissolved in DCM and dry loaded onto silica gel (2 mL). The residue was purified by column chromatography (25 g silica gel) eluting with 10 to 25% EtOAc/heptane to provide 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile (0.132 g, 67%): 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J=1.5, 1.1 Hz, 1H), 8.22-8.21 (m, 2H), 6.05 (s, 2H), 3.60-3.54 (m, 2H), 0.83-0.78 (m, 2H), −0.12 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[F:18][C:19]1[C:35]([F:36])=[CH:34][C:22]2[N:23]([CH3:33])[C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:25][C:21]=2[CH:20]=1>>[F:18][C:19]1[C:35]([F:36])=[CH:34][C:22]2[N:23]([CH3:33])[C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])=[N:25][C:21]=2[CH:20]=1
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Reactant: Cn1c(CC2CCCCN2)nc2cc(F)c(F)cc21
Product: Cn1c(CC2CCCCN2C(=O)c2nc(CO)sc2-c2ccc(F)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound (15 mg) was prepared from 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (84 mg) and (RS)-5,6-difluoro-1-methyl-2-piperidin-2-ylmethyl-1H-benzoimidazole, D61 (86 mg) by a procedure similar to that described for Example 4.
Reaction SMILES: [Li].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[ClH:20]>CCOCC.C(O)C>[ClH:20].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:6])=[NH:15]
Reactant: N#Cc1ccccc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: N=C(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of lithium-bis(trimethylsilyl)amide (10 g, 59.8 mmol) in ether (200 ml) in a flame-dried flask, was added 2-fluorobenzonitrile (7.26 g, 59.8 mmol) dropwise over 45 min. at r.t. The mixture was stirred for a further 4 h. at r.t. then cooled to −10° C. and 6N HCl in ethanol (40 ml) added dropwise over 30 min. (exothermic). After allowing the reaction mixture to warm to r.t. overnight the precipitate was filtered and washed with ether then dried under high vacuum at 40° C. overnight. To remove LiCl the dried solid was re-suspended in ethanol (200 ml) and filtered, then the volume reduce volume to ca. 30 ml. The solution was filtered then triturated with ether, and stirred 30 min. at 4° C. Filtration of the precipitate, washing with ether and high vacuum drying overnight at 40° C., afforded the title compound (7.8 g, 44.7 mmol, 75% yield) as a white solid. MS: m/e=138 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10].[CH3:33][NH:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([N:34]([CH3:35])[CH3:33])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10]
Reactant: CNC
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C(=O)N(C)C

Procedure:
A solution of Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (0.062 g, 0.12 mmol, Example 188), dimethylamine (0.06 mL, 2M solution in THF, Aldrich), HATU (0.05 g, 0.13 mmol) and triethylamine (0.018 mL, 0.13 mmol) was stirred at room temperature until complete by LCMS (about 30 min). The crude reaction mixture was slowly poured into water and the resulting white precipitate was filtered, washed with water and dried under vacuum to yield pure product (0.028 g). MS (ES) MH+: 532 for C21H27Cl2N5O5S; NMR: 1.20 (t, 3 H) 1.76 (s, 2 H) 2.18 (s, 3 H) 2.78 (s, 3 H) 2.93 (s, 3 H) 3.29 (d, 1 H) 3.36 (s, 3 H) 3.39-3.43 (m, 1 H) 3.55 (s, 1 H) 3.91 (s, 1 H) 4.15 (q, 2 H) 4.29 (s, 2 H) 7.15 (d, 1 H) 12.14 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.Cl.[F:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:38]3[CH2:39][CH2:40][C@H:36]([F:35])[CH2:37]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@H]1CCNC1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Agent: Cl
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CC[C@H](F)C3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 12c using (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and (S)-3-fluoropyrrolidine hydrochloride. LCMS (Method F): 542 (M+H)+, Retention time 4.9 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9]C2CCCCO2)[N:5]=[C:4]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:21])=[O:18])[N:3]=1.Cl>CC(C)=O>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:21])=[O:18])[N:5]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC2CCCCO2)n1
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(CO)n1
Yield: 81.4 %

Procedure:
A solution of 6 g of the product prepared in Example 4 in 50 ml of acetone was stirred with 3 ml of 1N aqueous HCl for 3 days at room temperature, concentrated at reduced pressure, and the residue was thoroughly washed with water to provide 4 g of the title compound, m.p. 140°-141°.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[N:28]C(OCC)=O)=[O:27])[CH:23]=[CH:24][CH:25]=4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.ClCCl.CO>CO>[CH:1]1([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[NH:28])=[O:27])[CH:23]=[CH:24][CH:25]=4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 94 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[4-(cyclobutylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (48 mg, 0.096 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 94% yield (39 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].N([O-])=[O:12].[Na+].FC(F)(F)C(O)=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:12])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(CO)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
m-Cyanobenzylamine (13.2 g), sodium nitrite (10.4 g), and dimethylformamide (100 ml) were mixed together, and the mixture was vigorously stirred at room temperature. Trifluoroacetic acid (22.8 g) was added dropwise to the mixture over one hour. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.9 g of m-cyanobenzyl alcohol (bp. 128-130° C./400 Pa) (yield 52%). The purity of the product was 98%.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.O>[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A suspension of 60% sodium hydride (54 mg, washed with n-hexane) in N,N-dimethylformamide (1 ml) was added slowly to a stirred solution of (2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (512 mg) in N,N-dimethylformamide (5 ml) under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. A solution of ethyl bromoacetate (225 mg) in N,N-dimethylformamide (1 ml) was added dropwise therein at the same temperature and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo to afford (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.59 g) as a crude oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[CH:9]=2)[CH2:4][CH2:3]1.[Li].Cl.[OH-].[Na+].[CH3:26]OC(OC)OC>FC(F)(F)C(O)=O.O1CCCC1>[CH3:26][NH:14][C:11]1[CH:12]=[N:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N
Reactant: COC(OC)OC
Agent: Cl
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
35 g (124 mMol) 6-(4-Methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine were dissolved in 273 ml ortho-formic acid trimethyl ester and 8 drops trifluoroacetic acid were added. The reaction mixture was refluxed for 3 hours then concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in 100 ml tetrahydrofuran and added dropwise at 0° C. to a suspension of 9.4 g (248 mMol) lithium alimunium hydride in 300 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour, cooled again to 0° C. and its pH was brought to 1 by careful addition of aqueous HCl 28%. After 5 minutes, the pH was raised to 10 by addition of aqueous NaOH 28%, the reaction mixture was filtered on Hyflo and concentrated under reduced pressure. The residue was chromatographed (eluent: dichloromethane/methanol 9:1) to yield 23.6 g (64%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)C1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclopentylsulfonyl)benzene MS (ESI): mass calcd. for C21H20FN3O2S, 397.13; m/z found, 398.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.65 (d, J=1.3, 1H), 8.30 (d, J=1.3, 1H), 8.19 (dd, J=7.9, 1.2, 1H), 8.14 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.48 (dd, J=7.5, 1.2, 1H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 3.23-3.15 (m, 1H), 1.92-1.81 (m, 2H), 1.77-1.63 (m, 4H), 1.60-1.51 (m, 2H).