Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49](=[O:50])[CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 480.4 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.0103 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (0.018 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described herein to afford crude 1,1-dimethylethyl {2-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-2-oxoethyl}carbamate (0.031 g) as an off-white solid. This material was treated with trifluoroacetic acid (0.30 mL, 3.89 mmol) in dichloromethane (1 mL) for 1 h. The solvent was evaporated to give the title compound (0.011 g, 40%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ ppm 11.60 (s, 1H), 10.23 (s, 1H), 8.97 (s, 1H), 8.04 (m, 3H), 7.91 (s, 1H), 7.77 (s, 1H), 7.40-7.54 (m, 2H), 7.29-7.40 (m, 2 H), 7.17-7.27 (m, 1H), 7.10 (s, 1H), 4.60 (s, 2H), 3.72 (s, 2H). MS: m/z 526 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][C@@H:19]2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)(=[O:8])=[O:9])=[C:11]([F:32])[CH:12]=2)[C@@H:19]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH2:20]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC(C)(C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(C)(C)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 88.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (293 mg, 0.467 mmol) prepared in Example 67e, triethylsilane (0.40 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (198 mg, 89%) as a colorless solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@@H:3]1[O:17][CH3:18].O=[CH:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(O)(C(F)(F)F)=O>>[CH:26]1([C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:1][C@H:2]2[C:11]([CH3:13])([CH3:12])[C:10]3[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=3[CH2:4][C@@H:3]2[O:17][CH3:18])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1N
Reactant: O=CCCNC(=O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1NCCCNC(=O)C1CCCCC1

Procedure:
Following the process of Example 11(c) using (6S,7S)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and cyclohexanecarboxylic acid (3-oxo-propyl)-amide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C24H37N3O3, 416.28; found, 416.6.
Reaction SMILES: [CH:1]1([CH:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH:1]1([CH:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1N)C1CC1
Yield: 670.2 %

Procedure:
(1-Cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.26 g, 0.71 mmol) and Na2S2O4 (1.00 g, 5.72 mmol) were treated substantially as described in Part E of Example 9 to yield 1.60 g (75%) of crude N2-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 336.3 [(M+H)+, 98].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O

Procedure:
2,3-dihydro-6-iodo-3-propyl-2-thioxo-4(1H)-quinazolinone is reacted with phosgene to give 2-chloro-6-iodo-3-propyl-4(3H)-quinazolinone ; and
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:40]1[CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[N:40]1([C:12]2[C:11]([CH2:10][C:9]3[CH:38]=[CH:39][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)([C:24]4[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=4)[OH:23])[CH:18]=3)[N:13]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: C1CNC1
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N3CCC3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (200 mg, 0.348 mmol, Intermediate 64), azetidine (199 mg, 3.48 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The vessel was then cooled to room temperature and the solvent was removed by reduced pressure distillation. The residue was taken up into EtOAc, transferred to a separatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C33H28Cl2N6O, 594.2. m/z found, 595.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.03 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.61-7.56 (m, 2H), 7.45 (dd, J=8.8, 2.2 Hz, 1H), 7.32-7.27 (m, 4H), 7.24 (d, J=1.1 Hz, 1H), 7.20-7.14 (m, 2H), 6.43 (t, J=2.1 Hz, 1H), 6.33 (d, J=1.2 Hz, 1H), 4.30 (s, 2H), 4.14 (t, J=7.6 Hz, 4H), 3.35 (s, 3H), 2.27-2.17 (m, 2H).
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:21][C:22]1[C:27]([C@@H:28]([N:30]2[CH2:35][CH:34]([CH3:36])[O:33][C@H:32](O)[C:31]2=[O:38])[CH3:29])=[CH:26][CH:25]=[C:24]([F:39])[N:23]=1.C(N(CC)CC)C.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[N:57]1[CH:61]=[C:60]([CH3:62])[N:59]=[CH:58]1)[CH:52]=O>C(#N)C>[F:21][C:22]1[C:27]([C@@H:28]([N:30]2[CH2:35][C@H:34]([CH3:36])[O:33]/[C:32](=[CH:52]\[C:51]3[CH:54]=[CH:55][C:56]([N:57]4[CH:61]=[C:60]([CH3:62])[N:59]=[CH:58]4)=[C:49]([O:48][CH3:47])[CH:50]=3)/[C:31]2=[O:38])[CH3:29])=[CH:26][CH:25]=[C:24]([F:39])[N:23]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CC1CN([C@@H](C)c2ccc(F)nc2F)C(=O)[C@@H](O)O1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(/C=C2\O[C@@H](C)CN([C@@H](C)c3ccc(F)nc3F)C2=O)ccc1-n1cnc(C)c1
Yield: 56.6 %

Procedure:
Triphenylphosphonium bromide (6.52 g) was added to a solution of (S)-4-[(S)-1-(2,6-difluoropyridin-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one (4.3 g) in acetonitrile, and the reaction solution was heated under reflux for one hour. Triethylamine (5.28 mL) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.42 g) were added to the reaction solution, which was then heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 2 N aqueous hydrochloric acid and ethyl acetate. Then, the aqueous layer was separated. The organic layer was washed with 2 N aqueous hydrochloric acid. Then, the total aqueous layers were combined and made alkaline with a concentrated sodium hydroxide solution. The organic layer was separated by extraction from the alkaline solution with ethyl acetate, and then washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using NH silica gel (heptane:ethyl acetate=1:1 to 0:100) to obtain 4.06 g of the title compound. The property values corresponded to those in Example 22.
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:5]1=2)=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@H:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:20]([CH3:22])=[CH:21][C:5]1=2
Reactant: [H][H]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Yield: 97 %

Procedure:
Shake a mixture of (S)-tert-butyl 5-azido-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.44 g, 3.89 mmol) and 5% palladium on charcoal (0.15 g, 50% wet) in methanol (50 mL) under 20 psi of hydrogen in a Parr bottle at room temperature for 12 h. Filter the mixture through Celite® and remove the solvents under reduced pressure to provide the title compound as a colorless oil (1.30 g, >99%), which is used in the next step without further purification. APCI MS m/z 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[CH:15]=[CH:14][S:13][C:12]=3[CH:11]=[C:10]([C:17]([OH:19])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].C(NCC)C.C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH:11]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c2ccsc2c1
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(-c2ccc(Cl)cc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 1, starting with 4-(4-chlorophenyl)benzo[b]thiophene-6-carboxylic acid (4.67 g) in toluene (45 cc) and thionyl chloride (3.6 cc) and then triethylamine (6.9 cc) and diethylamine (1.7 cc) in toluene (45 cc). After chromatography of the residue using a cyclohexane:ethyl acetate (90:10 by volume) mixture as the eluent, a residue is obtained, which is stirred for 2 hours in 40°-60° petroleum spirit. After filtering and drying, N,N-diethyl-4-(4-chlorophenyl)benzo[b]thiophene-6-carboxamide (1.07 g), m.p. 135° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+].CO>CC(=O)CC.C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:9][CH2:10][OH:11])[CH:3]=1
Reactant: OCCCl
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCC(C)=O
Product: OCCOc1cccnc1
Yield: 23.5 %

Procedure:
This compound was prepared according to the procedure in Preparation 19. Thus, reacting 14 g (0.15 mole) of 3-hydroxypyridine with 27 ml (0.4 mole) of 2-chlorethanol and 85 g of potassium carbonate in 150 ml of 2-butanone at reflux temperature gave 4.9 g of the title compound after column chromatography (5% methanol in methylene chloride on silica gel).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[OH:29][CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][OH:29])[CH:36]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: OCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 77.1 %

Procedure:
The method described in Example 152 was used to treat N-{2-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.2 g, 2.55 mmol) and 3-(hydroxymethyl)benzeneboronic acid (0.58 g, 3.8 mmol) in 1-propanol (15 mL) with triphenylphosphine (20.0 mg, 0.0760 mmol), aqueous sodium carbonate (3.82 mL of 2 M), water (3 mL), and palladium (II) acetate (5.7 mg, 0.025 mmol) with the following modifications. The reaction mixture was heated at reflux overnight. The crude product was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 0% to 35% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.98 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-1,1-dimethylethyl)methanesulfonamide as a white solid, mp 173-174° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22](=[O:23])[NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:27][CH2:26]4)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Yield: 90.8 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), 2-chloro-N,N-dimethylacetamide (0.023 mg, 0.18 mmol) and sodium carbonate (0.02 g, 0.18 mmol) were stirred at ambient temperature for 16 h in N,N-dimethylformamide (3 mL). The reaction mixture was evaporated. The residue was taken up in dimethylsulfoxide (1 mL) and subjected to preparative HPLC to yield the title compound (0.053 g, 87%) as a yellow oil; MS: m/e=487.8 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[F:13][C:2]([F:1])([F:12])[C:3]1[C:4]([CH2:5][OH:6])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(2-(2-(Trifluoromethyl)pyridin-3-yl)methanol (I-29A). A solution of 2-(trifluoromethyl)nicotinic acid (5 g, 26.2 mml) in dry tetrahydrofuran (50 mL) was cooled to −10° C. and then treated with LiAlH4 (39 mL, of a 1M solution in THF) by very slow addition. The reaction mixture was stirred at room temperature for 14 hours. The reaction was then cooled to −10° C. and quenched with a very slow dropwise addition of water (2 mL) and 6N HCl (1.2 mL). The reaction mixture was further diluted with water and extracted with dietyl ether (3×100 mL). The organics were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude oily residue was purified by silica gel chromatography with a gradient of 0-10% ethyl acetate-dichloromethane to yield (2-(trifluoromethyl)pyridin-3-yl)methanol (I-29A) as pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.61 (d, J=4.8 Hz, 1H), 8.15 (dd, J=8.0, and 0.8 Hz, 1H), 7.55 (dd, J=8.0 and 4.4 Hz, 1H), 4.95 (d, J=6.0 Hz, 2H), 2.02 (t, J=6.0 Hz, 1H). MS m/z 178.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C=C/C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
To a solution of ethyl (2E)-3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylate (0.62 g, 1.3 mmol) in tetrahydrofuran (5 ml)-methanol (5 ml) was added 1N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 12 hrs. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give (2E)-3-[3{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylic acid (0.41 g, yield 70%) as pale-yellow crystals.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.C(Cl)Cl.[CH2:23]([S:35](Cl)(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH2:23]([S:35]([N:10]1[CH2:9][CH2:8][CH2:7][S:6][C:5]1=[CH:4][N+:1]([O-:3])=[O:2])(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1.6 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine, 3.18 g of ethyldiisopropylamine and 20 ml of methylene chloride were mixed. The mixture was cooled to and stirred at -60° C. under a nitrogen atmosphere while 2.95 g of dodecanesulfonyl chloride was added in portions over a 10 minute period. The mixture was allowed to warm to 10° C. (2.5 hours), then stirred at 10° C. for 1 hour and at 20° C. for 1.5 hours. The resulting mixture was poured into water, and the organic phase was separated, dried (MgSO4), filtered and stripped of solvent. The residue, a gum, was chromatographed over silica gel, using methylene chloride as eluent. After workup the product was recrystallized from ethanol to give N-(dodecylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (3A) as a solid, m.p.: 116°-117° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1)([F:10])[CH3:9].O.[OH-].[Na+]>O1CCCC1>[F:7][C:8]([C:11]1[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)([F:10])[CH3:9]
Reactant: COC(=O)c1ccc(C(C)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (1.03 g, 27.3 mol) in tetrahydrofuran (30 ml) was dropwise added a solution of methyl 4-(1,1-difluoroethyl)benzoate (3.894 g, 18.18 mmol) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction solution was ice-cooled and water (1 ml), 15% aqueous sodium hydroxide solution (1 ml) and water (2.5 ml) were dropwise added successively to decomposed excess lithium aluminum hydride. The mixture was stirred as it was at room temperature for 2 hrs. The resulting precipitate was removed by filtration and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-1/1) to give the objective substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C#N)cc1
Yield: 88 %

Procedure:
In 4000 ml of acetone was dissolved 500 g (4.2 moles) of p-hydroxybenzonitrile and 965 g (5.0 moles) of octyl bromide, 828 g (6.0 moles) of anhydrous potassium carbonate was added thereto, and the mixture was refluxed with heating for 30 hours. Then, the inorganic salt was filtered off from the reaction mixture, acetone was distilled under reduced pressure. To the residue was added 2000 ml of ether and the mixture was washed with 2N aqueous solution of sodium hydroxide, water, then saturated aqueous solution of sodium chloride. The resulting organic layer was dried with anhydrous magnesium sulfate, and ether was distilled under reduced pressure to give 855 g of p-octyloxybenzonitrile (yield: 88%).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: Nc1ccccc1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1)=C1SCS1

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) and aniline (3.6 ml) in methylene chloride (100 ml) was stirred at room temperature for 8 hrs. The reaction mixture was washed with 10% aqueous sodium hydroxide solution, dil-HCl and water and then evaporated to dryness. The residue solid was purified with ethyl acetate to give the titled compound as a white solid. (7.9 g, 78%).