Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=O.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:33][C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2cccs2)CC1
Yield: 40.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-aminohexyl)piperidin-4-yl)-methyl)benzamide (2.0 g), 2-thiophenecarboxaldehyde (0.62 g), sodium borohydride (0.42 g) and ethanol (40 ml) were reacted and treated in the same manner as in Example 121 to give 1.0 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-thienylmethylamino)hexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>O>[Cl:24][S:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
4-(4-Nitrobenzyl)-phenylmethanesulfonic acid sodium salt (2.29 g) was combined with phosphorus pentachloride (1.45 g). The mixture was heated to 90° C. for 5 minutes, poured into water, and extracted with dichloromethane (3x 20 mL). Solvents were evaporated to give 4-(4-chlorosulfonylmethylbenzyl)-nitrobenzene as an impure yellow solid (0.63 g). This product was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[CH2:25]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=1[N:12]([CH2:15][C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:13]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cc(C)ccc2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 155 %

Procedure:
To a solution of 1.82 g (5.66 mmol) of the product of Example 4 in 20 ml DMF, was added NaH (60% suspension in oil, 498 mg, (12.5 mmol). The resulting mixture was stired for 15 minutes and benzyl bromide (4.84 g, 0.028 mol) was then added. The mixture was heated to 80-84° with stirnng for 18 hr under N2. The motion was then cooled to room temperature, diluted with ether, washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with EtOAc to afford 2.2 g (77%) of the desired product as a white solid. Electrospray Mass Spec: 502 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:17](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH:16]([CH3:35])[O:15][C:14]([CH3:37])([CH3:36])[C:13]=3[CH:38]=2)=[CH:5][CH:4]=1)#[N:2].N1CCCCC1>CN(C=O)C>[CH3:8][N:7]1[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[NH:17][CH:16]([CH3:35])[O:15][C:14]([CH3:37])([CH3:36])[C:13]=3[CH:38]=2)=[CH:5][CH:4]=[C:3]1[C:1]#[N:2]
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC1Nc2ccc(-c3ccc(C#N)n3C)cc2C(C)(C)O1

Procedure:
Prepared according to the procedure for Example 20 from 9H-fluoren-9-ylmethyl 6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.3 g, 0.6 mmol) and 20% piperidine in DMF. A white solid (0.07 g, 42%): mp 195-196° C.; 1H-NMR (DMSO-d6) δ 7.16 (d, 1H, J=2.8 Hz), 7.08 (dd, 1H, J=8.1, 1.9 Hz), 6.98 (d, 1H, J=4.1 Hz), 6.63 (d, 1H, J=8.5 Hz), 6.61 (s, 1H), 6.20 (d, 1H, J=4.1 Hz), 4.79-4.81 (m, 1H), 3.67 (s, 3H), 1.49 (s, 3H), 1.27 (d, 3H, J=5.5 Hz); MS (ESI) m/z 282 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)C2CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method F)=2.06
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:11][C:12]#[CH:13])[CH2:9][CH3:10])[CH3:7].[CH3:14][N:15]1[C:23]2[N:22]=[CH:21][N:20]([CH2:24][CH2:25][CH3:26])[C:19]=2[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:16]1=[O:35].Cl>CCCCCC.O1CCCC1>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:11][C:12]#[C:13][C:32]([OH:34])([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:17]1[C:18](=[O:27])[C:19]2[N:20]([CH2:24][CH2:25][CH3:26])[CH:21]=[N:22][C:23]=2[N:15]([CH3:14])[C:16]1=[O:35])[CH3:7]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C#CCN(CC)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
32.4 ml (52 mmol) of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise in 30 minutes to 5.8 g (52 mmol) of N,N-diethyl-2-propynylamine from stage C1) dissolved in 40 ml of tetrahydrofuran at between -60° C. and -65° C. The mixture was stirred at -70° C. for one hour and then warmed to room temperature, and a solution of 12.3 g (40 mmol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 60 ml of tetrahydrofuran was added dropwise over the course of 20 minutes, during which the temperature of the reaction mixture rose to 35° C. After stirring at room temperature for four hours, 100 ml of cold 1 N hydrochloric acid were added, the mixture was extracted by shaking several times with dichloromethane, the aqueous phase was made alkaline with sodium carbonate, the reaction product was extracted with dichloromethane, and drying of the sodium sulfate was followed by concentration under reduced pressure. The oily residue was purified by filtration through a silica gel column in chloroform/methanol (19:1) as eluent.
Reaction SMILES: C([Al]CC(C)C)C(C)C.[CH3:10][CH:11]([CH2:16][C:17](OC)=O)[C:12](OC)=O.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]>ClCCl.O>[CH3:12][C:11]1[CH:16]=[CH:17][N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:10]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)CC(C)C(=O)OC
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccn(-c2ccccc2O)c1
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Diisobutylaluminum (100 mL of 1.0 M, 100 mmol) was added dropwise to a solution of dimethyl 2-methylbutanedioate (7.6 g, 48 mmol) in dichloromethane (15 mL) at −78° C., and the solution was stirred for 1 h. A suspension of 2-aminophenol HCl salt (6.6 g, 45 mmol) in water (110 mL) was added initially dropwise with vigorous stirring, then in small portions. About midway through the addition, the cooling bath was removed to help facilitate stirring. The mixture was stirred vigourously at room temperature overnight, then filtered over celite and the filter cake was washed several times with dichloromethane. The filtrate was separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, concentrated and purified by column chromatography (0-40% EtOAc/hexane) to give 2-(3-methylpyrrol-1-yl)phenol (3.7 g, 48%) as a yellow oil. ESI-MS m/z calc. 173.2, found 174.3 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[CH3:19][C:18]([Si:15]([CH3:17])([CH3:16])[O:9][CH2:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(CCO)o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Reaction time: 2 h

Procedure:
To a solution of compound 21A (2.00 g, 15.9 mmol) in DMF (50 mL) was added imidazole (1.62 g, 23.9 mmol), followed by tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol). After 2 h at 25° C., the reaction was poured into diethyl ether (300 mL) and washed with water (1×100 mL), 1 N HCl (1×100 mL), water (1×100 mL), brine (1×50 mL) and dried over anhydrous MgSO4. Crude compound 204A was analyzed by LCMS and NMR and determined to be pure enough to be carried on directly to the next step. HPLC: 100% at 4.347 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:11])[C:9]#[CH:10]>[Cu]I.C(NCC)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]#[C:9][CH2:8][OH:11]
Reactant: C#CCO
Reactant: Brc1ccccn1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccccn1
Yield: 77 %

Procedure:
The mixture that consists of 16.6 ml (173 mmol) of 2-bromopyridine, 21.6 ml of propargyl alcohol, 2.5 g of palladium-bis-triphenylphosphine-dichloride and 173 mg of copper(I) iodide is mixed with 510 ml of diethylamine and heated for 1.5 hours to 80° C. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 17.8 g (134 mmol, 77%) of the title compound is isolated as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>CCO.C1COCC1.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Cl)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of example 85A (0.214 g, 0.505 mmol) in EtOH (2.52 mL) and THF (2.52 mL) was added platinum(IV) oxide (0.115 g, 0.505 mmol), and the resulting mixture was stirred at rt under 1 atm H2 overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give a mixture of the title compound and some dechlorinated product (4,4′-(trans-1-phenylpyrrolidine-2,5-diyl)dianiline).
Reaction SMILES: O[C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(Br)(=O)C([Br:13])=O>ClCCCl.CN(C=O)C>[Br:13][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1
Reactant: O=C(Br)C(=O)Br
Reactant: CC1(C)OC(=O)C=C1O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (2.1 g, 16.4 mmol) in DCE (40 mL) and DMF (1.5 mL) at 0° C. was added dropwise oxalyl bromide (3.0 mL, 32 mmol, 2 equiv). The mixture was stirred at room temperature for 4-5 h, and then put in an ice bath. Ice water (100 mL) was added slowly. The mixture was extracted with CH2Cl2 (100 mL). The organic phase was washed with 10% NaHCO3 and again with water, dried over sodium sulfate and evaporated to give the title compound 2.7 g (86% yield).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:28]1(CN)CCCC1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1CC1CCCC1
Reactant: NCC1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C1CCCC1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 36 %

Procedure:
1-Cyclopentylmethyl-6-quinolin-5-yl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)-pyrazin-2-ylamine (150 mg, 0.29 mmol), cyclopentylmethylamine hydrochloride (268 mg, 2 mmol), and triethylamine in ethanol (4 mL) was reacted and purified according to General Procedure E2 to give 25 mg (36% yield) of white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (dd, J=4.1, 1.6, 1H), 8.54-8.61 (m, 2H), 8.12 (d, J=8.2, 1H), 7.77-7.90 (m, 2H), 7.47-7.59 (m, 2H), 3.11-3.19 (m, 2H), 1.98-2.12 (m, 1H), 1.67-1.77 (m, 2H), 1.49-1.65 (m, 4H), 1.15-1.30 (m, 2H); MS (ESI) m/z 346.4 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:37])=[C:27]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:28]=1>>[C:29]([C:27]1[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[O:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3C(=O)c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-chloro-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.080 g. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H23O5Cl 486, found 487 and 489 (M+1 and M+3, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[S:24]([C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])(=[O:26])=[O:25])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)ccc1OC)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (23.00 g, 0.12 mol) in dichloromethane (0.70 L) and pyridine (0.10 L) was treated with 2-methoxy-5-methyl-benzenesulfonyl chloride (31.78 g, 0.14 mol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 0.5 N HCl (0.40 L), water (2 times 0.40 L) and brine (0.25 L) and the organic phase dried over sodium sulphate and evaporated. The residue was sonicated in ether/dichloromethane 95:5 and the precipitate filtered and dried under vacuum. 1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester was obtained as an off-white solid, 42.05 g (93%), MS (ISP): m/e=376.4 (M+H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[OH:30][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: ClCCl
Product: N#Cc1nnc(O)nc1N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 200 mg (0.67 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 10 ml of dichloromethane was cooled to 0° C. and treated with 332 mg (1.35 mmol) of 3-chloro-perbenzoic acid (70%). The reaction mixture was warmed up to room temperature and stirred overnight. For the working-up, the reaction mixture was diluted with 10 ml of dichloromethane and extracted twice with 10 ml of a saturated solution of sodium hydrogencarbonate. The combined organic phases were dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue, 170 mg of a yellow powder, was purified by chromatograhy on silica gel with a 98:2 mixture of dichloromethane and methanol as eluent. There were obtained 154 mg (86% of theory) of 3-hydroxy-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a yellowish solid; MS: 266 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:24]=[N:25][C:26](OC)=[CH:27][CH:28]=1.C(N(CC)CC)C>C(O)CCCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:26]3[N:25]=[N:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: COc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: COc1cc2nc(N3CCN(c4ccc(Cl)nn4)CC3)nc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazinoquinazoline (3.0 g, 10.4 mmole), 3-chloro-6-methoxy-pyridazine (3.96 g, 27.4 mmole) and triethylamine (5.0 g, 49.5 mmole) in n-pentanol (210 ml) were heated under reflux for 25 hours. The solvent was evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with chloroform followed by 5% methanol in chloroform. Further purification of the major product by HPLC using a Waters 500 Prep. LC/system, eluting with 6% by volume methanol in methylene chloride at a flow rate of 0.15 liters per minute gave the desired product which was recrystallized from methanol, m.p. 269°-270° C. (0.5 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[S:38][CH:39]=[C:40]([C:42](O)=[O:43])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:42]([C:40]3[N:41]=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[S:38][CH:39]=3)=[O:43])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)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: CC(=O)OC1CCc2c1ncc(NC(=O)c1csc(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (7.0 mg, 0.018 mmol), 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (5.2 mg, 0.022 mmol), HATU (17 mg, 0.045 mmol), DMF (0.042 mL) and DIPEA (7.0 mg, 0.054 mmol) were mixed together and the mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give pure sub-title compound as light yellow powder (3.7 mg, 34%). LCMS calc. for C30H34F2N5O5S (M+H)+: m/z=614.2. Found: 614.1.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[CH:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH:6]=[N:7][C:8]5[C:4]4=[N:3][CH:2]=[N:1][CH:9]=5)=[CH:15][CH:14]=3)=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:27][CH2:28]1)([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cncnc32)cc1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cncnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-purin-9-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 538.1 [M+H]+; tR=2.93 min (System 1); Rf=0.12 (CH2Cl2/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1>N1C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][S:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)(=[O:31])=[O:32])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)Nc1ccc(F)cc1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1)Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 45 °C
Reaction time: 48 h

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,5-diamine (example 43, step A+B, 200 mg, 0.727 mmol) was dissolved in 3 mL pyridine and 4-fluoro-phenylsulfamoyl chloride (298 mg, 1.42 mmol) was added. The reaction mixture was stirred at 45° C. for 2 days and quenched by addition of 50 mL water. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane, tetrahydrofurane 100:0->50:50 gradient). The title compound was obtained as a brown solid (43 mg, 13%), MS: m/e=449.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:10](=[O:12])[CH2:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 3-trifluoromethylphenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.