Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[N:64]([CH3:66])C)CCCCC1.NC1C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.COCCOC>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[NH:4][N:3]=[C:66]2[NH:64][C:59]1[CH:58]=[CH:63][CH:62]=[CH:61][CH:60]=1)(=[O:21])=[O:20])(=[O:30])=[O:29]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(Nc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
2-Methylsulfonyl-N-(3-phenylamino-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: the compound is prepared by reacting under microwave radiation on a Personal Chemistry Emrys Optimizer device. Four identical reactions are carried out. Each reaction is prepared as follows: 60 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate are placed in a Personal Chemistry SmithProcessVial™ tube with a maximum volume of 5 ml. 404 mg of cesium carbonate, 35.9 mg of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 12.1 mg of tris(dibenzylideneacetone)dipalladium[0] and 29 μl of aniline are then added. 4 ml of 1,2-dimethoxyethane are then added. The tube is sealed with the stopper provided for this purpose and the reaction is subjected to microwave radiation for 5 minutes at 120° C. The other parameters are those recommended by the constructor. The catalyst is filtered through Celite® 535 and the four reaction crudes are pooled, concentrated to dryness under reduced pressure in the rotary evaporator and purified by preparative LC/MS (conditions A). The fractions containing the protected intermediate compound are pooled and concentrated under reduced pressure. The yellow oil obtained is dissolved in 2 ml of dichloromethane and then 500 μl of trifluoroacetic acid are added. The solution is stirred for 2 hours at ambient temperature, until the starting product has disappeared. 10 ml of dichloromethane and 10 ml of a saturated sodium hydrogencarbonate solution are then added. When no more gas is being given off, the organic phase is dried over magnesium sulfate and the solvent is concentrated to dryness under reduced pressure and a rotary evaporator. 18.6 mg of 2-methylsulfonyl-N-(3-phenylamino-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of a yellow oil (analytical LC/MS analysis: Tr=3.49 minutes; [M+H]+=443.09).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:20]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN1CCCC1=O>[CH2:26]([N:8]1[C:6](=[O:7])[NH:5][NH:4][C:1]1=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
360 g of hydrazodicarbonamide, 807 g of stearyl amine and 1 ml of tin(II)dioctoate are stirred in 1 liter of N-methyl pyrrolidone for 4 hours at 175° C. and for 6 hours at 200° C. A deposit precipitates on cooling and is isolated by filtration under suction and washed with water, giving 955 g (90% of the theoretical) of 4-stearyl-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 118° to 120° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[S:8][C:9]3[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=3[C:4]=2[CH:3]=1.[CH:16]1[C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][C:17]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[S:8][C:9]3[CH:14]=[CH:13][C:12]([C:29]4[CH:30]=[CH:31][C:32]5[C:33]6[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=6)[C:21]6[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:27]=5[CH:28]=4)=[CH:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
Reactant: Clc1cc2c(cn1)sc1ccc(Br)cc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc2c(cn1)sc1ccc(-c3ccc4c5ccccc5c5ccccc5c4c3)cc12
Temperature: 25 °C
Yield: 69 %

Procedure:
The mixture of 3-chloro-6-bromo-[1]benzothieno[2,3-c]pyridine (1.7 g, 5.8 mmol), triphenylen-2-ylboronic acid (1.6 g, 5.8 mmol), potassium phosphate tribasic (3.7 g, 17 mmol), 200 mL toluene and 10 mL water was prepared and bubbled with nitrogen for twenty minutes. Then the tris(dibenzylideneacetone)dipalladium (53 mg, 0.060 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (96 mg, 0.23 mmol) were added. The mixture was bubbled with nitrogen for another twenty minutes. After refluxed overnight under nitrogen, then reaction mixture was cooled to room temperature and filtered through a silica plug and washed with dichloromethane. The first several portions were discarded since they only contained impurities. The combined filtrate was concentrated to give crude product, which was recrystallized from hot dichloromethane and hexanes to give 1.8 g 3-chloro-6-(2-triphenyleneyl)-[1]Benzothieno[2,3-c]pyridine as yellow solid (4.0 mmol, 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2OC1C=C2C(=CC=1)C=C(NC(OCC1C=CC=CC=1)=O)C=C2.[Br:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[C:44]([F:48])=[C:43]([OH:49])[CH:42]=[CH:41]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:49][C:43]1[CH:42]=[CH:41][C:40]2[C:45](=[CH:46][CH:47]=[C:38]([Br:37])[CH:39]=2)[C:44]=1[F:48]
Reactant: COc1cc2nccc(Oc3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)c2cc1OC
Reactant: Oc1ccc2cc(Br)ccc2c1F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (prepared as in Example 1, Step b)(371 mg, 1.66 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Step a, 400 mg, 1.66 mmol) and DMAP (203 mg, 1.66 Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40-100% EtOAc in hexanes) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 428.0 (M+1). Mass Calc'd for C21H15BrFNO3: 427.02.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1ccncc1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccncc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31b using pyridine-4-methanol (0.4 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.4 g). Yield 0.47 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:21])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[C:28]([NH:31][CH2:32][CH:33](O)[CH2:34][NH:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:28]([NH:31][CH2:32][CH:33]([O:19][C:18]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([F:21])[CH:11]=2)[CH2:17][CH2:16]1)=[O:20])[CH2:34][NH:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29]
Reactant: CC(=O)NCC(O)CNC(C)=O
Reactant: O=C(O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NCC(CNC(C)=O)OC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (0.30 g, 0.92 mmol) was dissolved in dry DCM (30 mL); two drops of DMF and oxalyl chloride (78 uL, 0.92 mmol) were added; and the reaction mixture was stirred at r.t. under nitrogen atmosphere for 30 minutes. Additional oxalyl chloride (39 uL, 0.46 mmol) was added and the reaction was stirred for 15 minutes. This solution was added dropwise to a solution of N-(3-acetylamino-2-hydroxypropyl)acetamide (synthesized as reported on J. Org. Chem., 2000, 65(4), 1200, which is incorporated herein by reference in its entirety) and triethylamine (385 uL, 2.76 mmol) in dry DCM (2 mL) and dry DMF (2 mL). 4-Dimethylaminopyridine (34 mg, 0.28 mmol) and dry pyridine (1.5 mL) were added, and the reaction mixture was stirred overnight at r.t. The reaction mixture was extracted with DCM/H2O, and the organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by gradient flash chromatography (eluent DCM to DCM/methanol 97/3 v/v) affording the title compound which was further purified by preparative HPLC to obtain 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 2-acetylamino-1-(acetylaminomethyl)ethyl ester (105 mg, 24% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH2:13].CCO>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(Br)c1
Yield: 88 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2M solution of methylamine in EtOH (10.8 mL, 22 mmol) to give the title compound (4.3 g, 88%) as a white solid. MS (ISP) 250.0[(M+H)+].
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][CH2:21][CH:22](O)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:23]1([CH2:22][CH2:21][CH2:20][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CCC(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.204 g (1.5 mmol) of phenylpropanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=2:1) to obtain the product as a oil (0.27 g).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[C:13]([CH3:24])[S:12][C:11]=1[N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])=[O:9])C.Cl>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[S:12][C:13]=2[CH3:24])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(N2C(=O)c3ccccc3C2=O)sc(C)c1CCc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(N2C(=O)c3ccccc3C2=O)c(C(=O)O)c1CCc1ccc(Br)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(4-bromophenyl)ethyl]-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5-methy-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 30, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [C:1]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][C:31]#[CH:32].N1CCCCC1>C1COCC1.CCOCC.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.[Cu]I>[Si:5]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:33])[CH:11]=[CH:12][CH:13]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](OCc1cccc(I)c1)(c1ccccc1)c1ccccc1
Reactant: C#CCCCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cccc(C#CCCCCO)c1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of t-Butyl-diphenyl(3-iodo-benzyloxy)silane (8.49 g, 18 mmol) in THF (70 mL) is added hex-5-ynol (2.5 mL, 22 mmol) and (Ph3P)4Pd (990 mg, 0.85 mmol) and CuI (171 mg, 0.9 mmol). This solution is degassed and placed under an argon atmosphere. To this solution is added piperidine (5.4 mL, 54 mmol) and stirring continued for 4 h. The reaction mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as an oil (6.84 g). 1H NMR (300 MHz, CDCl3): δ 7.70 (m, 4H), 7.40 (m, 6H), 7.27 (m, 4H), 4.71 (s, 2H), 3.71 (t, 2H), 2.47 (t, 2H), 1.74 (m, 4H), 1.10 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:13]1=[O:27]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:16]2[CH:15]=[CH:14][C:13](=[O:27])[N:12]([CH3:11])[CH:17]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Product: Cc1cc(-c2ccc(=O)n(C)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.05 min; Mass spectrum (ESI+): m/z=292, 294 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)(OC(C)(C)C)=O.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(C2CCNC2)CC1
Temperature: 25 °C

Procedure:
1-N-BOC-3-pyrrolidinone (500 mg, 2.70 mmol), benzyl-1-piperazinecarboxylate (595 mg, 2.70 mmol) and titanium (IV) isopropoxide (960 mg, 3.37 mmol) are stirred under argon for 1 hour. Ethanol (3 ml) and sodium cyanoborohydride (113 mg, 1.80 mmol) are added and the reaction mixture stirred at room temperature over night. The compound is purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% TFA), followed by deprotection using trifluoroacetic acid (5 ml). The solvent is removed in vacuo and the compound is partitioned between chloroform and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)[C:7]#[N:8])[CH3:3].C(C1C=NC=C(CCC(C)C)C=1)#N>>[CH:12]([C:10]1[CH:9]=[C:6]([CH2:7][NH2:8])[CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[N:11]=1)([CH3:14])[CH3:13]
Reactant: C=C(C)c1cc(C#N)cc(C(=C)C)n1
Agent: CC(C)CCc1cncc(C#N)c1
Product: CC(C)c1cc(CN)cc(C(C)C)n1

Procedure:
(2,6-diisopropylpyridin-4-yl)methanamine was synthesized from 2,6-di(prop-1-en-2-yl)isonicotinonitrile following the general procedure as described for 3-cyano-5-isopentylpyridine.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: CN1CCNCC1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)N1CCN(C)CC1
Yield: 100 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.354 g) obtained in Example 9 and N-methylpiperazine (0.119 ml) to give (±)-4-[(3,5-Dichloro-4-pyridyl)aminocarbonyl]-7-methoxy-3-[(4-methylpiperazin-1-yl)carbonylmethyl]-2,3-dihydrobenzofuran (0.427 g, 100%) as an oily substance. The obtained free base was dissolved in ethyl acetate (50 ml), and a saturated solution of hydrochloric acid in ethyl acetate (2 ml) was added thereto followed by stirring. The precipitated hydrochloride was collected by filtration and washed with ethyl acetate to give Compound 17 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1.[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([O:40][CH3:41])[C:26]=1[OH:42]>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]3[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([N:21]([CH3:22])[CH3:23])[CH2:17][CH2:16]2)[CH:28]=[C:27]([O:40][CH3:41])[C:26]=1[OH:42]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C#N)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C#N)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, 6-bromo-4-((trans-4-(dimethylamino)cyclohexyl)amino)quinoline-3-carbonitrile (28 mg, 0.075 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (32 mg, 0.113 mmol) to afford the desired product (11.9 mg, 35%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.46-8.40 (m, 2H), 8.02 (dd, J=8.7, 1.9 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 4.48-4.38 (m, 1H), 3.99 (s, 3H), 2.50-2.39 (m, 1H), 2.35 (s, 6H), 2.29 (d, J=11.8 Hz, 2H), 2.06 (d, J=12.0 Hz, 2H), 1.73-1.61 (m, 2H), 1.59-1.47 (m, 2H). ESI MS m/z 451 [C25H27ClN4O2+H]+; HPLC 98.8% (AUC), tR=10.61 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][NH:32]C(=O)COC)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(OC(=O)C(O)=O)C>>[NH2:32][CH2:31][CH2:30][C:29]([NH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:38]
Reactant: COCC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CCOC(=O)C(=O)O
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (20-2) of Example 20 was repeated except for using oxalic acid monoethylester and 0.09 g of the compound obtained in (20-1) of Example 20 instead of methoxyacetic acid, and subjecting column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.04 g, 37%).
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[N:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=2)[O:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2cccc(OCc3ccccc3)c2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2-ylamine (55 mg, 0.462 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (252 μL, 1.81 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (58 mg, 22%).