Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[N:38][NH:37][C:36]4=[O:40])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:37]1[C:36](=[O:40])[N:35]([C:32]2[CH:33]=[CH:34][C:29]([N:26]3[CH2:27][CH2:28][N:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[CH2:24][CH2:25]3)=[CH:30][CH:31]=2)[CH:39]=[N:38]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Product: COc1ccc(N2CCN(c3ccc(-n4cnn([C@H](C)[C@@]5(c6ccc(F)cc6F)CO5)c4=O)cc3)CC2)cc1
Yield: 30.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 543 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 809 mg of 4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone prepared by a method described in Journal of Medicinal Chemistry, vol. 27, page 894 (1984), 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone (373 mg) was obtained as colorless prisms.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][CH2:30][CH3:31])[N:20]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][O:27][CH3:28])[CH3:25])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][CH2:30][CH3:31])[N:20]([CH2:21][CH2:22][CH2:23][CH:24]([N:26]([O:27][CH3:28])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH3:25])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)N=C=O
Reactant: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)NOC
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)N(OC)C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl isocyanate (0.35 mL, 3.58 mmol) was added to a solution of N-[4-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-O-methylhydroxylamine (1.25 g, 2.99 mmol) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) to provide 1-[4-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-3-isopropyl-1-methoxyurea as a tan powder, mp 101-103° C. MS (APCI) m/z 503.3 (M+H+); Anal. calcd for C29H38N6O2 0.85H2O: C, 67.25; H, 7.73; N, 16.22. Found: C, 66.84; H, 7.64; N, 15.89.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]>ClCCl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: CNCCN1CCOCC1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of N-methyl-2-morpholinoethanamine (2.1 g, 13.12 mmol, 1.00 equiv, 90%) in dichloromethane (20 mL) at 0-5° C. was added triethylamine (1.47 g, 14.55 mmol, 1.00 equiv) followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (3.3 g, 15.00 mmol, 1.20 equiv, 90%) in dichloromethane (10 mL). The resulting solution was then stirred for 3 h at room temperature. The mixture was diluted with 100 mL of dichloromethane, washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine, dried over sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (20:1) to afford 4.4 g (99%) of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:43]([OH:45])=O)=[CH:34][N:35]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1>C(Cl)Cl>[S:48]1[CH:49]=[CH:50][N:51]=[C:47]1[NH:46][C:43]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[N:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:34]=1)=[O:45]
Reactant: CCCCCn1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCn1cc(C(=O)Nc2nccs2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
A solution of triphenylphosphine (355 mg, 1.35 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (240 mg, 1.35 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-pentyl-1H-indole-3-carboxylic acid (300 mg, 1.13 mmol). The reaction was stirred at 0° C. for 10 min and then was allowed to warm to 25° C. where it was stirred for 1 h. The reaction was then treated with 2-aminothiazole (283 mg, 2.83 mmol) and stirred at 25° C. for 3 d. At this time, the reaction was partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 10% aqueous hydrochloric acid solution (15 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×30 mL), water (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded 6-chloro-1-pentyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (101 mg, 25%) as a pink solid: mp 139-141° C.; EI-HRMS m/e calcd for C17H18ClN3OS (M+) 347.0859, found 347.0859.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:16]([C:18]([CH3:20])=O)[CH3:17]>[Pt].O>[CH:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH:1]([CH2:2][CH3:3])[CH3:9])=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([CH2:18][CH3:20])[CH3:17]
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: CCC(C)=O
Agent: [Pt]
Solvent: O
Product: CCC(C)Nc1ccc(Cc2ccc(NC(C)CC)cc2)cc1
Temperature: 136 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
4,4′-Methylenebis(benzeneamine) (19.8 g, 0.1 mol), methyl ethyl ketone (20.0 g, 0.28 mol), Pt(S)/C (2.0 g), and water (28.0 g; formed a second phase) were charged into reactor. The reactor was purged 3 times with H2 at 22° C. The reaction mixture was then stirred at 800 rpm at 136° C. under H2 for 2.5 hours. GC showed 100% conversion of 4,4′-methylenebis(benzeneamine), and a 96-97% yield of N,N′-di-sec-butyl-4,4′-methylenebis(benzeneamine).
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])=S)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:41]#[C:42][NH2:43]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20](=[N:43][C:42]#[N:41])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Reactant: N#CN
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(F)(F)F)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Yield: 89.5 %

Procedure:
The product of Example 34C (0.97 g, 1.9 mmol), triethylamine (1.1 mL, 7.8 mmol), cyanamide (0.25 g, 5.8 mmol) and Hg(OAc)2 (1.2 g, 3.9 mmol) in acetonitrile (15 mL) were processed as described in Example 16E to provide the title compound (0.84 g, 1.7 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 1.73-1.86 (m, 1H), 1.85-1.98 (m, 1H), 2.01 (s, 3H), 2.21-2.48 (m, 4H), 3.98 (s, 3H), 4.77 (s, 2H), 6.63 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.60-7.71 (m, 2H); MS (DCI/NH3) m/z 509 (M+H)+. Anal. calculated for C24H27F3N4O3S; C, 56.68; H, 5.35; N, 11.02. Found: C, 56.50; H, 5.10; N, 10.67.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:15][N:16]([CH2:18]N(C)C)[CH3:17].C(Cl)(=O)C>ClCCl>[CH3:15][N:16]([CH2:18][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH3:14])[C:2]=2[Cl:1])[NH:6][CH:5]=1)[CH3:17]
Reactant: CN(C)CN(C)C
Reactant: CCCOc1ccc2[nH]ccc2c1Cl
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCOc1ccc2[nH]cc(CN(C)C)c2c1Cl
Yield: 78.8 %

Procedure:
Treatment of 4-chloro-5-n-propyloxyindole (5.10 g, 24.3 mmol) with bis (dimethylamino)methane (BDAM) (3.34 g, 32.7 mmol) and acetyl chloride (2.57 g, 32.7 mmol) in dichloromethane by the method described in 1 (c) gave 3-dimethylaminomethyl-4-chloro-5-n-propyloxyindole (5.11 g) as a sticky solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>C1COCC1.CO.O>[CH2:13]([C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[C:3]([C:1]#[N:2])[N:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)OC)cc(C#N)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cc(C(=O)O)cc(C#N)n1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-ethylisonicotinate (0.233 g, 1.23 mmol, Eq: 1.00) was diluted in THF (12.1 ml) and MeOH (1.46 ml). At 2-3° C., 1M LiOH in water (1.53 ml, 1.53 mmol, Eq: 1.25) was added dropwise (over 3 min) The RM was stirred at 2-3° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. White solid. MS (EIC): 174.9 ([M−H]−)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:39]1(I)[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: IC1CCCC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCCC3)cc2n1Cc1ccccc1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (1.0 ml) was reacted with K2CO3 (38 mg, 0.28 mmol), cyclopentyl iodide (53 μl, 0.46 mmol) to yield the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][S:13][C:7]4=[N:6][C:5]=3[CH3:14])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:22]=1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCS2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3)CC1)CCS2

Procedure:
A mixture of 3.3 parts of 6-(2-chloroethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 8 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered hot over Hyflo and the filter-cake was washed with trichloromethane. The filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 2 parts of 6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 165.6° C. (compound 1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Oc3cccc(C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Oc2cccc(COc3ccc(CCC(=O)O)cc3)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a solution of methyl 3-(4-{[3-(3-methylphenoxy)benzyl]oxy}phenyl)propanoate (0.380 g, 1.01 mmol) in a mixture of methanol (4 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.214 g, yield 58%) as colorless prism crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].Cl.N>C(OCC)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccccn1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNc1ccccn1
Temperature: 95 °C
Reaction time: 50 h

Procedure:
A mixture of 2-aminopyridine (200 g) and ethyl acrylate (468 g) was heated to 90-100° C. and then stirred for 50 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Ethyl acetate was added to the reaction mixture and treating the reaction mixture with hydrochloric acid, followed by ammonia. Both the organic and aqueous layers were separated, the organic layer was washed with sodium chloride solution and then distilled off the solvent completely from the organic layer to get title compound as a residue. Yield: 295 grams.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][O:20]CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH2:11][C@H:10]([CH2:9][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)[CH:29]([CH3:31])[CH3:30])[C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:17])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](CO)C(C)C)C(C)C)ccc1OC
Temperature: -78 °C

Procedure:
A solution of 1 g of the pyrrolidine 8 in 17 mL of THF is cooled to −78° C. and 17 mL of ammonia condensed into the flask. To the mixture is added 0.44 g of Sodium and the resulting dark-coloured mixture stirred over night at −78° C. To the mixture is added 2.6 g of ammonium chloride. The mixture is allowed to warm to r.t. (ammonia evaporates off and unreacted sodium is dissolved) before addition of 40 mL of toluene and 1.9 g of acetic acid. After 10 min 25 mL of water is added and the phases are separated. The aqueous phase is back-extracted with 25 mL of toluene, then the combined organic phases are washed four times with 1:1 water-brine before drying over sodium sulfate and evaporating in vacuum. Purification of the crude oily product (0.86 g) on silica gel, eluting with ethyl acetate-heptane affords e.g. 0.71 g of pure 9a. 1H-NMR (CDCl3, 300K): 6.8 (2H), 6.7 (1H), 4.7 (1H), 4.1 (2H), 3.8 (3H), 3.5-3.7 (5H), 3.4-3.5 (1H), 3.4 (3H), 2.7-2.8 (1H), 2.4-2.5 (3H), 2.0-2.2 (2H), 1.5-1.8 (8H), 1.4 (9H), 0.8-0.9 (12H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](=O)([O:34]C1C=CC=CC=1)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:18](=[CH:17][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:15][CH:14]=3)[N:19]([C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:20]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C=O)c1ccc2c3ccc(OCc4ccccc4)cc3n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (140 mg, 0.42 mmol) in 5 mL dry THF at 0° C. under Ar atmosphere was added NaH (50 mg, 60% in oil, 1.26 mmol) in 4 portions. The mixture was then stirred at rt for 20 min followed by the addition of tert-butyl phenyl carbonate (244 mg, 1.26 mmol) with a syringe. The reaction was allowed to stir at rt for 3 h and quenched onto ice (30 g). The mixture was extracted with EtOAc (2×40 mL) and the combined organic phase was dried over MgSO4. After solvent removal, the residue was chromatographed to afford tert-butyl 2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a white solid (120 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.39 (m., 2H), 7.37-7.32 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 1.75 (s, 9H); MS (ESI) m/z 431 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>C(Cl)Cl>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)N=C=O
Reactant: Nc1nc2ccccc2s1
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Three and one half parts by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution at room temperature of 41/2 parts by weight of 2-aminobenzothiazole dissolved in 150 parts by weight of methylene chloride. After stirring the reaction mixture at room temperature for 12 hours, the product was isolated by filtration giving a 40% yield of essentially pure methyl 4-(benzothiazol-2-yl)allophanate having a melting point of 338°-340° C with decomposition.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Ca+2]>CCO.C(Cl)(Cl)Cl>[CH2:8]([O:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCNOCc1ccccc1
Yield: 75.4 %

Procedure:
Trifluoroacetic acid (TFA, 16 mL) was added to (B) (2.59 g, 8.51 mmol), and the solution stirred at room temperature for 20 min (Drierite tube). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (3) (75% yield), which has been previously prepared: NMR δ1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][N:20]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNCC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2CC1

Procedure:
The title compound was prepared in analogy to Example 89 from N-(3-chloro-4-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-d]azepin-4-amine from Example 85A (100 mg, 0.29 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (66 mg, 0.40 mmol) to yield 89 mg (67%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:10]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[C:9]([Cl:10])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.42 g of 3-t-butyl-1H-pyrazole was dissolved to 230 ml of chloroform. 1.55 g of N-chlorosuccinimide was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.62 of 3-t-butyl-4-chloro-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.33 g, 1.0 mmol) and commercially available 4-pyridineboronic acid (0.184 g, 1.5 mmol) according to the general procedure IVb. Obtained as a light red solid (0.034 g, 9%). MS (ISP) 370.0 [(M+H)+]; mp 153.5° C.