Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][OH:2])[CH:19]=[CH:18][C:16]=1[NH2:17]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2CO)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Part A: 2-Fluoro-4-((2′-tert-butyldimethylsilyloxymethyl)phenyl)aniline: A solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) and 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) in THF (80 mL) and aqueous Na2CO3 solution (2M, 80 mL) was bubbled with nitrogen for 10 minutes. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 hours. The THF layer was separated and filtered through a pad of silica gel. The silica gel was washed with THF. To the combined filtrates containing 2-fluoro-4-(2′-formylphenyl)aniline (65 mL) was portion by portion added NaBH4 (2.2 g, 29.1 mmoL). The resulting mixture was stirred at room temperature for 1 hour, quenched with 1N HCl (10 mL), and washed with 1N HCl (100 mL×3). The combined HCl layers were neutralized with 50% NaOH to pH 12 and extracted with EtOAc (100 mL×3). The EtOAc layers were dried over Na2SO4, concentrated, and purified by column chromatography with a graduate solvent (hexane to EtOAc) to give 2-fluoro-4-(2′-hydroxymethylphenyl)aniline (3.83 g, 97.6%). 1H NMR (CDCl3) δ7.53 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.25 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.06 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=1.8 Hz, 1H), 6.82 (t, J=8.8 Hz, 1H), 4.63 (s, 2H), 3.79 (bs, 2H); 19F NMR (CDCl3): δ−135.66 (dd, J=12.21 Hz, J=9.2 Hz); CIMS(CI) m/z 218 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[C:14](=O)[CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=[O:5])[CH3:2].[CH3:16]N(C=O)C.CC(N(C)C)=O.Cl.[NH:28]([C:32]1[CH:33]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)[C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[C:14]3[N:31]=[C:29]([NH:28][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([S:38](=[O:39])(=[O:40])[NH2:41])[CH:33]=4)[N:30]=[CH:16][C:13]=3[CH2:12][CH2:11][C:9]=2[N:10]=1)=[O:5])[CH3:2]
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1nc2c(s1)C(=O)CCC2
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1nc2c(s1)-c1nc(Nc3cccc(S(N)(=O)=O)c3)ncc1CC2
Temperature: 120 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
To 7-oxo-4,5,6,7-tetrahydro-benzothiazole-2-carboxylic acid ethyl ester (0.1128 g, 0.50 mmol) was added DMF/DMA solution (3 mL) and the mixture was refluxed under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the resulting crude product (6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-benzothiazole-2-carboxylic acid ethyl ester) was taken through to the next step without further purification. The above was dissolved in anhydrous DMA (3 mL) and treated with 3-guanidino-benzenesulfonamide hydrogen chloride (128 mg, 0.51 mmol) and powdered potassium carbonate (35 mg, 0.26 mmol). The mixture was heated to 120° C. with vigorous stirring for 12 hours. The mixture was cooled down to room temperature, and diluted with water. The resulting solid was filtered, rinsed with more water, a little bit of iPrOH and Et2O. The crude solid was purified by silica gel to give the title compound as a brown solid in 24% yield (52 mg). MS (ES+) 432, (ES−) 430. δH (d6 DMSO) 1.36 (3H, t), 3.05 (2H, t), 3.17 (2H, t), 4.42 (2H, q), 7.33 (2H, s), 7.41 (1H, d), 7.50 (1H, t), 7.89 (1H, d), 8.43 (1H, t), 8.52 (1H, s), 10.04 (1H, s).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[O:37][C:33]=2[CH:32]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:45]=[CH:44][C:34]3[N:35]=[C:36]([NH:38][C:39]([CH:41]4[CH2:42][CH2:43]4)=[O:40])[O:37][C:33]=3[CH:32]=2)[CH:28]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)oc4c3)c2)c1
Yield: 74.1 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (222 mg, 1.72 mmol), thionyl chloride (1 mL, 13.7 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (126 mg, 407 μmol) produced in Example B1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (68.5 mg, 561 μmol) as starting materials, and in the same manner as in Example B1(viii), the title compound (145 mg, 74%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[N:23]([CH3:32])[C:22]1=[O:33].C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@H:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[N:23]([CH3:32])[C:22]2=[O:33])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Reactant: CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CCc2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1

Procedure:
100 mg of 19 (0.39 mmol), 88.42 mg of 8a (0.39 mmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2.0 ml of THF are successively introduced into a Wheaton tube, with agitation and under an argon atmosphere. The agitation is maintained at AT for 24 h. The reaction medium is directly evaporated to dryness. The crude is chromatographed on a silica cartridge (12 g, eluent EtOAc), and 60 mg of expected product Ex6 (white solid) are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([NH2:14])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:23](=[O:29])[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:24](=[O:25])[C:23](=[O:29])[N:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)CCNc1nc(Cl)ncc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a stirred solution of 2-chloro-N4-(3-methylbutyl)pyrimidine-4,5-diamine (2.8 g, 13.08 mmol) in toluene (40 mL) was added triethylamine (4.23 g, 41.88 mmol) and ethyl chlorooxoacetate (1.95 g, 14.33). The mixture was then heated to reflux for 16 h. It was then cooled to rt, the bulk of solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (eluent: 70% ethyl acetate in hexane) afforded the desired product (2.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.01 (d, J=6.6 Hz, 6H), 1.60-1.82 (m, 3H), 4.20-4.35 (m, 2H), 8.35 (s, 1H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@H:13]([F:27])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:28][C:29]1[C:38]([F:39])=C(F)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:28][C:29]1[C:38]([F:39])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@H:13]([F:27])[CH2:12]2)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@@H](F)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 18 h
Yield: 42.7 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml). After adding a 5% palladium-carbon catalyst (moisture content: 55.6%, 500 mg), the mixture was stirred under a hydrogen atmosphere for 18 hours. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (8 ml) and 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) were added thereto. Then the mixture was stirred under a nitrogen atmosphere at 100° C. for 26 hours. After allowing it to cool, dimethyl sulfoxide was removed by evaporation. The residue was dissolved in chloroform (80 ml), and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: chloroform:methanol=9:1) followed by concentration of the eluate under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was added dropwise into the residue followed by stirring at room temperature for 20 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×2) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide followed by washing with chloroform (100 ml×2). The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (200 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol and dried under reduced pressure to obtain 170 mg (42.6%) of the title compound as a yellow powder.
Reaction SMILES: B.[CH2:2]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[O:18][CH2:17][C:16]2=O)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].Cl>C1COCC1>[CH2:2]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[O:18][CH2:17][CH2:16]2)[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1CCN(CCCN2C(=O)COc3ccc(C)cc32)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC1CCN(CCCN2CCOc3ccc(C)cc32)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A solution of borane in THF (1M, 0.5 mL, 0.5 mmol) was added to a solution of 4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one (50 mg, 0.15 mmol) in THF (6 mL). The reaction mixture was stirred at 40° C. for 16 h then aqueous HCl (4M, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred for 16 h then concentrated in vacuo. A solution of K2CO3 (0.5 g) in water (5 mL) was added and the product was extracted with dichloromethane (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified on an Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethyl acetate in heptanes+1% Et3N). Yield: 29.2 mg, 56%. HPLC-MS: M+1+=373.5 (UV/MS (%)=95/90). 1H NMR (400 MHz, CDCl3): δ=0.90 (3H, t), 1.18-1.35 (9H, m), 1.68 (2H, broad d), 1.78 (2H, quin.), 1.89 (2H, broad t), 2.24 (3H, s), 2.35 (2H, t), 2.89 (2H, broad d), 3.27 (2H, t), 3.31 (2H, t), 4.19 (2H, t), 6.39 (1H, broad d), 6.52 (1H, broad s), 6.66 (1H, d). 13C NMR (CDCl3): δ 14.3, 21.4, 23.1, 24.2, 29.3, 32.8 (2C), 36.1, 36.6, 47.4, 49.3, 54.5 (2C), 56.5, 64.7, 113.0, 116.2, 117.7, 131.1, 135.3, 142.0.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][CH2:15]2)[C:8]([O:11]C)=[N:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][CH2:15]2)[C:8](=[O:11])[NH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ncc(S(C)(=O)=O)cc1CN1CCC(CCc2ccccc2OCC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CS(=O)(=O)c1c[nH]c(=O)c(CN2CCC(CCc3ccccc3OCC3CCCCC3)CC2)c1
Yield: 94.7 %

Procedure:
In ethanol (10 ml) was dissolved 138 mg of 1-[(5-(methylsulfonyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethyloxy)phenyl]ethyl]piperidine. To the mixture was added 1 ml of thionyl chloride, followed by heating under reflux for 2.5 hours. An aqueous sodium carbonate aqueous solution was added to the reaction solution, and the resulting precipitates were collected by filtration, to give 127 mg of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:14]=[CH:13][CH:12]([O:15][CH3:16])[O:11][CH3:10]
Reactant: O=Cc1ccccc1Br
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COC(C=Nc1ccccc1Br)OC

Procedure:
2-bromobenzaldehyde (18.4 g, 0.1 mol) and 2,2-dimethoxyethanamine (11.55 g, 0.11 mol) in 200 mL of toluene was heated to reflux for 4 hr. The reaction mixture was evaporated under vacuum to give an oil of 2-bromo-N-(2,2-dimethyoxyethylidene)aniline which was used for the next step without purification. The oil was dropped into 50 mL of concentrated H2SO4 and the mixture was heated to 130-140° C. for 30 mins, then the reaction mixture was poured into 500 mL if ice-water and adjust to pH˜8 with 5N sodium hydroxide solution. The aqueous solution was extracted with DCM (250 mLX5) and washed with water (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum. The crude solid was purified with silica gel to give 8-bromoisoquinoline (2.2 g, two steps 10.6%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1N.[BH3-][C:18]#[N:19].[Na+]>CO>[CH2:1]([NH:16][C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[NH:19][CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: [BH3-]C#N
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN[C@H]2CCCC[C@@H]2NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Benzaldehyde (6.36 g, 60 mmol) was added dropwise over a period of 2 minutes to a solution of (S,S)-cyclohexane-1,2-diamine (3.42 g, 30 mmol) in 50 mL of anhydrous MeOH at refluxing temperature. After stirring for 30 min, the solution was allowed to cool to room temperature and NaBH3CN (2.4 g, 63 mmol) was added in portions. After the vigorous effervescence subsided down, the mixture was brought to refluxing and stirred for 20 min. The reaction was quenched by water and extracted with dichloromethane. The organic phase was dried and concentrated to give 8.5 g of crude product (yield 95%) which was used in the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C([N:37](CC)CC)C.[CH:42]([NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([NH:45][C:46]1[C:51]([NH:37][C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])=[CH:50][CH:49]=[CH:48][N:47]=1)([CH3:44])[CH3:43]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)Nc1ccccn1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)Nc1cccnc1NC(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (0.5 mL) at room temperature. The reaction was heated at reflux for 1 h then was concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and 2-(isopropylamino)pyridine (136 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS) then quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid 2-(isopropylamino)pyridylamide. MS m/z 577.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][C:3]=1[CH3:16].CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:15][O:14][C:5]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][C:2]([CH:26]=[O:27])=[C:3]([CH3:16])[CH:4]=1
Reactant: COCCCOc1cc(Br)c(C)cc1OC
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCOc1cc(C=O)c(C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-methoxy-5-(3-methoxy-propoxy)-2-methyl-benzene (2.50 g, 8.65 mmol) in THF (25 mL), cooled to −70° C., is added a 1.6M solution of n-buthyllithium in hexane (5.94 mL, 9.51 mmol). After 30 min, DMF (1.05 mL, 13.0 mmol) is added and stirring is continued overnight while the reaction mixture is gradually warmed to room temperature. Quenching with ice-cold 1N aqueous HCl is followed by extraction with diethyl ether. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 7:2) gives the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.29. MS: 239.2 [M+H]+. 1H-NMR (CDCl3): δ 2.16 (m, 2H), 2.66 (s, 3H), 3.39 (s, 3H), 3.60 (m, 2H), 3.97 (s, 3H), 4.18 (m, 2H), 6.73 (s, 1H), 7.40 (s, 1H), 10.2 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.P(=O)(O)(O)O.[CH2:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>C1C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[O:1][C:2]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:18][CH2:19]1
Reactant: C=CC(=C)C
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CC1(C)CCc2c(ccc3[nH]c(=O)ccc23)O1

Procedure:
6-hydroxyquinoline-2-one (481 mg) and orthophosphoric acid (0.55 ml) were dissolved in 5 ml of benzene, and then a solution of 0.55 ml of isoprene in 5 ml of benzene was added thereto with stirring. The resulting mixture was heated under reflux for 30 minutes. The reaction liquid was poured into ice-cold water and extracted with ethyl acetate. The extracted liquor was washed with water, dehydrated by addition of anhydrous sodium sulfate and filtered. The solvent in the filtrate was distilled away under reduced pressure, and the resulting residue was recrystallized from ethanol to give 567 mg of pale yellow needle-like crystals.
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH:15]=[C:10]3[CH2:11][NH:12][CH2:13][CH2:14][C:9]3=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[CH2:17][N:12]3[CH2:13][CH2:14][C:9]4=[N:8][N:7]([CH:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH:15]=[C:10]4[CH2:11]3)[CH2:21][CH2:22]2)[CH2:29][CH2:28][CH2:27]1
Reactant: c1c2c(nn1C1CCCC1)CCNC2
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2nn(C3CCCC3)cc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-cyclopentyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine hydrochloride (143 mg, 0.63 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (136 mg, 0.63 mmol), K2CO3 (348 mg, 2.52 mmol) and KI (10 mg, 0.06 mmol) in CH3CN (10 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (10 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×10 mL) and the combined extracts are washed with brine (20 mL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 372.3; 1H NMR (δ, CDCl3): 7.10 (s, 1H), 4.51-4.60 (m, 1H), 3.64 (q, 4H), 3.54 (s, 2H), 3.36 (s, 2H), 2.77-2.83 (m, 4H), 2.64-2.74 (m, 1H), 2.25-2.32 (m, 4H), 1.62-2.62 (m, 14H).
Reaction SMILES: I[CH3:2].[O:3]=[S:4]1(=[O:16])[CH2:9][C:8](=O)[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]1[CH3:15].[C:17]([O-:20])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:15][N:5]1[C:6]2[CH:7]=[CH:11][CH:12]=[CH:13][C:14]=2[C:17](=[O:20])[C:9]([CH3:8])([CH3:2])[S:4]1(=[O:3])=[O:16]
Reactant: CN1c2ccccc2C(=O)CS1(=O)=O
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1c2ccccc2C(=O)C(C)(C)S1(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Iodomethane (187 ul, 426 mg, 3 mmol) is added dropwise to a suspension of 2,2-Dioxo-1-methyl-2,1-benzothiazin-4(3H)-one ([CAS: 7117-31-9], 220 mg, 1 mmol), K2CO3 (1.38 g, 10 mmol) in 3 mL of dry DMF at room temperature. The resulting mixture is stirred at 60° C. After 2 h, the reaction mixture is filtered, and washed with ethyl acetate (20 mL). The combined solution is concentrated and the residue is purified by flash column (ethyl acetate-heptane v/v 10%) and gives the title compound as white solid (190 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C1COCC1>[CH3:29][S:30]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)(=[O:32])=[O:31]
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 57 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with methanesulfonyl chloride (0.012 mL, 0.15 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 23 h. Obtained as a yellow solid (38 mg).