Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nccc(-c2cccc(CNCCc3cccnc3)c2)n1
Product: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 18 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>O1CCOCC1.CCOC(C)=O>[CH2:20]([NH:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=[C:2]([NH:3][CH2:4][CH2:5][CH2:6][CH3:7])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3c2)cc1
Reactant: CCCCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCNc1nc(NCCCC)c2cc(-c3ccc(F)cc3)ccc2n1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 2,4-Dichloro-6-(4-fluoro-phenyl)-quinazoline (20 mg, 0.068 mmol) in 1,4-dioxane was added n-butylamine (20 mg). The solution was heated to 60° C. for 2 hours, and subsequently cooled, diluted with EtOAc and washed with brine. The organic layer was dried and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (8 mg). The product was characterized as follows: MS (m/z): 367 ([M+H]+, 100); HPLC Rt=1.69 minutes (Method A).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:5]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: Cc1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 0.95 g of 2-methylfluorene, 2.17 g of 4-picolylchloride hydrochloride, 50 mg of cetyl(Bu)3PBr, 30 ml toluene, and 5 ml 50% NaOH by reaction at 50° for 6 hrs. The material was chromatographed to yield 0.2 g product. NMR (CDCl3, 200 MHz) δ: 2.47(s,3H), 3.37(s,4H), 6.49(d,J=5.3 Hz,4H), 7.03-7.45(arom.H), 8.09(d,4H). HRMS calculated for C26H22N2 : 362.1783 Found: 362.1778
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>ClCCl.CO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: OC1CCN(c2ccnc(Cl)n2)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2nccc(N3CCC(O)CC3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 1-(2-chloropyrimidin-4-yl)-4-piperidinol (120 mg, 0.534 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (109 mg, 0534 mmol) using in analogous manner the procedure described in example 43b). Obtained after trituration in dichloromethane/methanol (19:1 v/v) as a white solid (117 mg, 57%). MS ISP (m/e): 381.1 [(M+1-1)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.24 (s, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 7.63 (s, 1H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.03 (s, 1H), 6.31 (d, 1H), 4.77 (d, 1H), 4.07 (m broad, 2H), 3.78 (s, 3H), 3.77 (m, 1H), 3.25 (m broad, 2H), 2.14 (s, 3H), 1.78 (m broad, 2H), 1.36 (m broad, 2H). Mp 197-200° C.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[N:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH:25]1([C:22]2[N:23]=[CH:24][C:19]([C:2]#[C:1][N:3]3[C:11]4[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=4[C:5]4[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]3=4)=[CH:20][CH:21]=2)[CH2:27][CH2:26]1
Reactant: Brc1ccc(C2CC2)nc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(C3CC3)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 6.9 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (102 mg, 0.45 mmol), 5-bromo-2-cyclopropyl-pyridine (75 mg, 0.38 mmol), dichlorobistriphenylphosphine palladium(II) (7 mg, 0.0114 mmol) and TBAF.3H2O (359 mg, 1.14 mmol) was heated at 80° C. for min by microwave. After completion of reaction (monitored by TLC), the mixture was poured into water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum to obtain crude product, which was purified by reverse phase chromatography to obtain 9 mg of 5-(6-cyclopropyl-pyridin-3-ylethynyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.58 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.18 (s, 1H), 7.08 (m, 2H), 3.65 (s, 2H), 2.90 (m, 4H), 2.60 (s, 3H), 2.42 (s, 3H), 2.05 (m, 1H), 1.05 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:25](=[O:27])[CH3:26])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (300 mg) was dissolved in 1.5 ml of dry pyridine. Acetic anhydride (1.5 ml) was added thereto. The resulting mixture was stirred at room temperature for 5 hours, diluted with water, extracted with ether, washed successively with brine, dilute hydrochloric acid, brine, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-acetoxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH3:58])[C:52]([CH3:60])([CH3:59])[CH2:51]2)[NH:47][C:46]1=[O:61])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:43])[CH2:25][N:26]3[C:30](=[O:31])[C:29]4([CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH3:39])[C:33]([CH3:41])([CH3:40])[CH2:32]4)[NH:28][C:27]3=[O:42])=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[CH2:62](Br)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]>CN(C)C=O>[CH2:62]([O:43][CH:24]([CH2:25][N:26]1[C:30](=[O:31])[C:29]2([CH2:36][C:35]([CH3:37])([CH3:38])[N:34]([CH3:39])[C:33]([CH3:40])([CH3:41])[CH2:32]2)[NH:28][C:27]1=[O:42])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:4]([O:3][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:13][CH2:10][CH2:9][CH2:8][CH2:7][CH2:12][CH3:11])[CH2:44][N:45]3[C:49](=[O:50])[C:48]4([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH3:58])[C:52]([CH3:60])([CH3:59])[CH2:51]4)[NH:47][C:46]3=[O:61])=[CH:12][CH:11]=2)([CH3:15])[CH3:14])=[CH:17][CH:18]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)cc3)cc1)C2=O
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)N(C)C(C)(C)C4)C3=O)OCCCCCCCCCCCC)cc2)cc1)CN1C(=O)NC2(CC(C)(C)N(C)C(C)(C)C2)C1=O
Reaction time: 2 h

Procedure:
1.5 g of sodium hydride was added, with stirring, to a solution of 8.2 g of 2,2-bis{4-[2-hydroxy-3-(7,7,8,9,9-pentamethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane, prepared as described in Example 1, in 150 ml of N,N-dimethylformamide, and the mixture was stirred at 50°-60° C. for 2 hours. 10.0 g of n-dodecyl bromide were then added dropwise to the mixture and the whole mixture was heated at 50°-60° C. for two hours and then at 70°-80° C. for a further 4 hours, stirring all the time. After completion of the reaction, the reaction mixture was condensed by evaporation under reduced pressure and then 200 ml of benzene were added to the resulting residue. This solution was then washed with, in turn, a 2% w/w aqueous solution of sodium carbonate and water. The washed solution was dried over anhydrous potassium carbonate and then the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 32:4:5:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine, giving the desired Compound No. 34 as a colourless, viscous liquid, having an Rf value of 0.53 on thin-layer chromatography on silica gel using a 20:2:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine as developing solvent.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 38A and 32 mg (0.26 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 31 mg (42% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:11]1([CH2:14][C:15]#[N:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCN1CCNCC1
Reaction time: 14 h

Procedure:
To a solution of 30% TFA/CH2Cl2 (10 mL) is added 4-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 6.8 mmol) and the reaction is stirred for 14 h. The reaction is concentrated and chromatoghraphed using silica gel (%1 NH4OH/7% MeOH/CH2Cl2) to isolate piperazin-1-yl-acetonitrile as the free base. 1H NMR (300 MHz, CDCl3) δ4.36 (s, 2H), 3.54 (s, 2H), 3.45 (t, 2H), 3.13 (t, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[C:6]([S:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH:5]=1)([OH:3])=[O:2].FC(F)(F)C(O)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[O:13]=[C:11]1[C:23]2[CH:22]=[C:21]3[C:17](=[CH:16][C:15]=2[S:14][C:6]2[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=[CH:8][C:7]=2[CH2:10]1)[CH2:18][CH2:19][CH2:20]3
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1Sc1ccc2c(c1)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1C(=O)C2)CCC3

Procedure:
4-Carboxy-2-(5-indanylthio)phenylacetic acid (33.55 g, 0.102 mole) was added to trifluoroacetic acid (200 ml) and to the stirred suspension was added, slowly with stirring, trifluoroacetic anhydride (200 ml). After stirring the mixture for 48 hours at room temperature, the mixture was poured slowly onto ice (200 g), and the slurry was diluted to about 1 liter before collecting the crude product. The dried solid was stirred in suspension in acetonitrile for 45 minutes, refiltered and dried to yield 24.95 g.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[N:18]=[C:19]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[S:20][C:21]=2[NH:22]C(=O)OC(C)(C)C)=[O:16])[CH2:4][CH2:3]1.Cl>O1CCOCC1>[NH2:22][C:21]1[S:20][C:19]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:18][C:17]=1[C:15]([NH:14][C:9]1[CH:10]=[N:11][N:12]([CH3:13])[C:8]=1[CH:5]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)CC1

Procedure:
tert-Butyl 4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate was stirred with 4.0M HCl in dioxane (5 mL) for 2 h. Solvent was removed in vacuo, and the residue was basified with sat. sodium bicarbonate and extracted with ethyl acetate 3×. Combined organic layers were concentrated and purified via reverse phase HPLC to give 369. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.35 (s, 1H), 7.60-7.36 (m, 3H), 7.27 (t, J=8.7 Hz, 1H), 3.80 (s, 3H), 2.77 (t, J=12.3 Hz, 1H), 2.13-1.94 (m, 2H), 1.67 (dt, J=29.6, 13.3 Hz, 5H). MS (ESI) m/z: 433.2 [M+H+].
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:10]=1[NH2:11]>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:10]=1[NH:11][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: Cc1cccc(C)c1N
Reactant: CCCS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1c(C)cccc1C

Procedure:
A solution of 1-propanesulphonyl chloride (25 ml) in toluene (50 ml) was added during 15 minutes to a stirred solution of 2,6-dimethylaniline (55 ml) in toluene (400 ml). The mixture was stirred and boiled under reflux for 20 hours, then cooled and filtered. The toluene solution was washed with dilute hydrochloric acid (3 times) and water, then extracted (3 times) with dilute sodium hydroxide solution. The aqueous alkaline solution was acidified with dilute hydrochloric acid, and the product collected by filtration, washed with water and dried. Crystallisation from toluene/60°-80° petrol gave 2',6'-dimethyl-1-propanesulphonanilide as buff coloured crystals (28.0 g, 55%), melting point 72°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[CH3:10][C:11]([CH3:13])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH:11]([CH3:13])[CH3:10])[CH3:5]
Reactant: CNc1ccccc1Br
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)N(C)c1ccccc1Br
Reaction time: 72 h

Procedure:
To a solution of 2-bromo-N-methylaniline (2.07 g, 11.22 mmol), in dichloroethane (45 mL) was added acetone (1.31 g, 22.5 mmol), AcOH (4.04 g, 67.32 mmol) and Na(OAc)3BH (7.14 g, 33.66 mmol) sequentially at RT. The mixture was stirred for 72 h. The reaction was cooled with ice bath, and 2M NaOH (100 mL) was added slowly, then stirred for 5 min. The organic layer was separated, washed with brine dried and solvent removed. The crude product contained a mixture of 2:1 ratio of Compound 219 and starting material. This mixture was used as is in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1OCC
Yield: 63.6 %

Procedure:
The compound was prepared according to general procedure E with 3-ethoxy-4-hydroxybenzaldehyde (2.4 mmol) in dry acetone (15 ml), anhydrous K2CO3 (3.1 mmol), and ethylbromoacetate (3.6 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 565 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 385 mg of purified compound were obtained (63% yield). 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.0 Hz, 3H), 1.49 (t, J=7.0 Hz, 3H), 4.18 (q, J=7.0 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 4.79 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.45 (s, 1H) 9.86 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 14.0, 14.5, 61.2, 64.4, 65.9, 111.2, 113.0, 125.5, 131.0, 149.1, 152.7, 168.1, 191.5. MS (ESI): m/z 253.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:37](=[NH:39])[NH2:38])[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:39]=[C:37]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[N:38]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: N=C(N)C1(O)C=CC=C(C(F)(F)F)C1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 1. Yield: 60 mg (59% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:38][O:39][C:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:40]3([O:39][CH3:38])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC1=CCCCC1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
To a solution of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-hydroxymethyl-1H-imidazole (14) (33 mg, 0.1 mmol) prepared in accordance with the method as described in WO 96/10019 and p-toluenesulfonic acid pyridinium (27.6 mg, 0.11 mmol) in toluene (1.5 mL) was added 1-methoxycyclohexene (112 mg, 1.00 mmol) under ice-cooling, and stirred at room temperature for 6 hours. A drop of triethylamine was added to the reaction mixture, and the mixture was filtered to remove the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on an alumina column (eluate: toluene) to give the compound 15 (37.0 mg, 70%) as oil. Rf 0.16 (Al2O3 60, Type E, toluene).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)=[CH:21][CH:22]=1)[CH3:41]
Reactant: CCN(CC)CCOS(C)(=O)=O
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Temperature: 50 °C
Yield: 41.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give 6-(4-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 8.06-7.90 (m, 4 h), 7.58 (s, 1H), 7.42 (t, 1H, J=7.6 Hz), 7.03-7.00 (m, 2H), 6.23 (d, 1H, J=7.2 Hz), 6.05 (d, 1H, J=8.1 Hz), 4.57 (brs, 2H), 4.27 (brs, 1H), 3.67 (brs, 1H), 3.52-3.41 (m, 3H), 3.22-3.20 (m, 4 h), 2.16-2.06 (m, 3H), 1.80 (brs, 1H), 1.45 (t, 6H, J=6.9 Hz), 1.28 (d, 3H, J=6.3 Hz). LC/MS: 486 [M+H]+, tR=1.12 min. HPLC: 98.72% at 214 nm, 99.10% at 254 nm, tR=5.46 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[C:18]=1[CH3:27])(=[O:3])[NH2:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[C:18]=1[CH3:27])(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C)c3C)c2cc1C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1C(N)=O
Yield: 82.8 %

Procedure:
The title compound (840 mg) was obtained from 7-methoxy-4-chloroquinoline-6-carboxyamide (890 mg) and 4-nitro-2,3-dimethylphenol (940 mg), in the same manner as Production Example 7. Next, 6-carbamoyl-4-(2,3-dimethyl-4-nitrophenoxy)-7-methoxyquinoline (840 mg) was dissolved in tetrahydrofuran (25 ml) and methanol (25 ml), and the solution was subjected to catalytic reduction with palladium-carbon (840 mg) for 10 hours under a hydrogen atmosphere to obtain the title compound (639 mg).
Reaction SMILES: C1([C@H]([N:9]([C@@H:21]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:23]=3[CH2:22]2)[CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C)C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:37]([O:36][C:34]([CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:24]2[CH2:25][CH2:26][CH2:27][C@@H:21]([NH:9][CH2:10][C@@H:11]([OH:20])[CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][C:23]=2[CH:31]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](N(C[C@@H](O)COc1ccccc1)[C@H](C)c1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](NC[C@@H](O)COc1ccccc1)CCC2
Yield: 85.8 %

Procedure:
A mixture of (2R)-1-[N-((R)-1-phenylethyl)-((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (2.0 g) and 10% palladium on activated carbon (50% wet, 0.70 g) in ethanol (24 ml) and tetrahydrofuran (12 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours, and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel to afford (2R)-1-[((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (1.37 g).