Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[NH2:6][C:7]1[C:14]([Cl:15])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=1.C(N(CC)CC)C.Cl>C(OCC)(=O)C.O>[Cl:15][C:14]1[CH:13]=[C:10]([CH:11]=[O:12])[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[NH:6][C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: COc1cc(N)c(Cl)cc1C=O
Reactant: C=CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1cc(OC)c(C=O)cc1Cl
Temperature: 35 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acrylic acid (commercially available, for example, from Aldrich) (46 ml, 0.67 mol) was added slowly to a stirred suspension of 4-amino-5-chloro-2-methoxybenzaldehyde (Step B) (50.0 g, 0.27 mol) and triethylamine (204 g, 2.02 mol) in ethyl acetate (0.85 L) at 25° C. Propanephosphonic anhydride (50% in ethyl acetate; 429 g, 0.67 mol) was added over 30 minutes keeping reaction temperature at 30-40° C. The mixture was stirred at 30-40° C. for a further 1 hour and then cooled to 25° C. and diluted with water (0.26 L) and acidified with 32% hydrochloric acid (108 g) to pH 2-3. The organic layer was separated and washed with a mixture of water (0.23 L) and 32% sodium hydroxide (14 g)—aqueous layer ca. pH 7. The organic phase was washed with water (0.23 L) and then concentrated under reduced pressure (ca. 300 mbar) to remove 0.56 kg of distillate. Methylcyclohexane (335 g) was added and then a further 286 g of distillate was removed under reduced pressure. Methylcyclohexane (111 g) was added and then the resulting suspension was cooled to 20° C., filtered and washed with methylcyclohexane. The cake was dried at 40° C. under reduced pressure for 12 hours to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (46 g, 71%)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])=[O:5])C.C(O)C>O1CCCC1>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c3c(c1)c(O)c(C(=O)N1c4ccccc4CC1C(=O)O)c(=O)n3CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5Hpyrido[1,2,3-de]-1,4-benzoxazine (2.8 g), 1N-sodium 35 hydroxide (20 ml), ethanol (20 ml) and tetrahydrofuran (20 ml was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid to give precipitates, which were collected and washed with ethanol to afford crystals of 2,3-dihydro-6-(2-carboxy-1-indolinylcarbonyl)-7- hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4 -benzoxazine (1.6 g).
Reaction SMILES: O[CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cnc2c(c1)CCCC2O
Reactant: O=S(Cl)Cl
Product: Cc1cnc2c(c1)CCCC2Cl
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 8-hydroxy product of Example 1 (15 g.) was added portionwise to thionyl chloride (33 g.) at 0° C and the mixture stirred at 0° C for 1 hour and heated at reflux for an additional 2 hours. The solvent was removed in vacuo and the residual oil heated at reflux for 1 hour with ethanol (15 ml.) to remove excess thionyl chloride. The resultant precipitate was recrystallised from ethanolether to give 8-chloro-3-methyl-5,6,7,8-tetrahydroquinoline hydrochloride as colourless needles (17.4 g.) m.p. 177° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:31])[CH2:19][C:20]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:31])[CH2:19][C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(CC(=O)OCC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)OCC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-(tert-butoxy)-2-oxoethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetate (Fmoc-MeGly-HOGly-OtBu) (Compound SP637) (2.30 g, 5.41 mmol) in methylene chloride (18 mL) was mixed with triisopropylsilane (2.78 mL, 13.5 mmol) and trifluoroacetic acid (5.41 mL, 70.3 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetoxy)acetic acid (Fmoc-MeGly-HOGly-OH) (Compound SP638) (2.00 g, 5.41 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ClC1C(C)=C(N[C@H]([C@@H](O)C)C(O)=[O:40])C=CC=1C#N.OC1C=C(C=CC=1)C(NN)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:40])[CH:22]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: NNC(=O)c1cccc(O)c1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O)c2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
Intermediate 7a was synthesized similarly to the procedure outlined for intermediate 1b described above using (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (522 mg, 1.9 mmol) and 3-hydroxy-benzohydrazide (296 mg, 1.9 mmol). After column chromatography (EtOAc), the title compound was isolated as a white solid (407 mg, 52%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.80 (br s, 1H), 9.52 (br s, 1H), 8.76 (br s, 1H), 7.49 (d, J=8.7 Hz, 1 H), 7.40 (m, 1H), 7.29 (at, J=8.1 Hz, 1H), 7.04 (m, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.55 (d, J=7.1 Hz, 1H), 4.89 (br s, 1H), 4.39 (m, 1H), 4.11 (dd, J=3.3, 7.0 Hz, 1H), 2.35 (s, 3H), 1.34 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:57]=1[S:63](Cl)(=[O:65])=[O:64]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:57]1[CH:58]=[CH:59][C:60]([CH3:62])=[CH:61][C:56]=1[O:55][CH3:54])(=[O:65])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(C)cc1OC)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with 2-methoxy-4-methylbenzenesulfonyl chloride to afford (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methoxy-4-methyl-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (20 mg) was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z):. 919.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:34](Cl)(Cl)=[O:35].[F:38][C:39]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:40]=1[NH2:41]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]=2)[C:34]([NH:41][C:40]2[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:39]=2[F:38])=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCn1nnc(NC2CCCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1nnc(N(C(=O)Nc2ccc(F)cc2F)C2CCCCC2)n1
Temperature: 45 °C

Procedure:
To a stirred mixture of N-cyclohexyl-2-dodecyl-2H-tetrazol-5-amine (0.3349 g, 0.0009981 mol) and diisopropylethylamine (1.7 mL, 0. 0098 mol) at room temperature under nitrogen atmosphere was added a 12.5 wt/wt % solution of phosgene in toluene (8 mL). The mixture was heated at 45° C. for 22 hours and allowed to cool. Excess phosgene was removed, and the mixture was rotoevaporated to a sludge. The residue was suspended in anhydrous tetrahydrofuran (25 mL), additional diisopropylethylamine (0.35 mL, 0. 0020 mol) and 2,4-difluoroaniline (0.11 mL, 0.0011 mol) were added, and the mixture was refluxed for 6 days. The mixture was partitioned between diethyl ether and 1M hydrochloric acid. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), and rotoevaporated to an oil. The oil was chromatographed twice on silica gel: (80 g, 230-400 mesh) using PET ether-acetone (7:1) and (68 g, 230-400 mesh) using PET ether-acetone (40:1) to give the title compound as a yellow oil, yield 0.2995 g (61%). 1H NMR (CDCl3): δ 9.9 (s, 1H) , 8.2 (m, 1H) , 6.9 (m, 2H), 4.6 (m, 3H), 2.1 (m, 4H), 1.8 (m, 4H), 1.6 (m, 2H), 1.3 (m, 20H), 0.9 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])#[N:2].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoate (1.40 g, 3.50 mmol) in ethanol (10 ml) and THF (10 ml) was added a 1 N aqueous sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material. The resultant material was recrystallized from ethyl acetate and hexane.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:45])[CH2:14][NH:15][C@H:16]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:17]([N:19]1[CH2:22][CH2:21][C@H:20]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)=[O:24])=[O:18])(C)(C)C>C(Cl)Cl>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[C:27]([CH:32]=1)[CH2:26][NH:25][C:23]([C@@H:20]1[CH2:21][CH2:22][N:19]1[C:17](=[O:18])[C@H:16]([NH:15][CH2:14][C:13]([OH:45])=[O:12])[CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)=[O:24]
Reactant: CC(C)(C)OC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1)C1CCCCC1
Reaction time: 16 h

Procedure:
TFA (5 mL) was added to a solution of tert-butyl({(1R)-2-[(2S)-2-({[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]amino}carbonyl)azetidin-1-yl]-1-cyclohexyl-2-oxoethyl}amino)acetate (22 mg, 0.04 mmol) in CH2Cl2 (5 mL) at 0° C. After stirring for 16 h the reaction mixture was concentrated. The title compound was isolated by reverse phase HPLC. LCMS (M+H): 489.3. 1H NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 8.22 (s, 1H), 7.67 s, 1H), 7.50 (m, 2H), 4.79 (m, 1H), 4.45–4.20 (m, 5H), 3.91 (m, 3H), 2.61 (m, 1H), 2.21 (m, 1H), 1.87–1.72 (m, 5H), 1.37–1.17 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([OH:20])[C:18]=1[OH:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([S:14][CH3:15])=[S:13])[CH2:8][CH2:7]1.[C:21](Cl)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:20][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([O:1][C:17](=[O:20])[CH3:16])[C:18]=1[O:19][C:2](=[O:1])[CH3:18])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([S:14][CH3:15])=[S:13])[CH2:10][CH2:11]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CSC(=S)N1CCN(Cc2cc(O)c(O)c(O)c2)CC1
Solvent: c1ccncc1
Product: CSC(=S)N1CCN(Cc2cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c2)CC1
Yield: 113 %

Procedure:
To 395 mg (1.0 mmol.) of methyl 4-(3,4,5-trihydroxybenzyl)-1-piperazinecarbodithioate was added 2 ml of dry pyridine. To the resulting suspension was added 0.22 ml (3.1 mmol.) of acetyl chloride under chilling with ice. The mixture was then stirred, and further stirred overnight at room temperature. The mixture was then extracted with ethyl acetate after addition of water. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and processed to distill off the solvent. The residue was purified by silica gel column chromatography and crystallized from ether to give 249 mg of the desired compound as a white crystalline product, m.p. 141°-143° C., yield 63.4%.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.[F:16][C:17]([F:48])([F:47])[O:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][NH:24][C:25]([C@H:27]2[CH2:32][NH:31][CH2:30][CH2:29][N:28]2[S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[O:26])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:48][C:17]([F:16])([F:47])[O:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][NH:24][C:25]([C@H:27]2[CH2:32][N:31]([C:2]3[S:3][C:4]4[C:9]([Cl:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=4[N:15]=3)[CH2:30][CH2:29][N:28]2[S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:38][CH:37]=2)(=[O:34])=[O:35])=[O:26])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C2CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a mixed solution of the compound (27 mg) obtained in Example 1001, Step 8, the compound (43 mg) obtained in Step 4 and chloroform (0.50 ml) was added N,N-diisopropylethylamine (19 μl) under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (66 mg).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH:24]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[H-].[Na+]>C1COCC1>[CH:24]1([S:29][C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH:2]([F:23])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: SC1CCCC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1SC1CCCC1
Yield: 107.1 %

Procedure:
This compound was prepared as described in Example 108: 3 g (0.0083 mol) of product of Example 103, 1.02 g (0.01 mol) of cyclopentylmercaptan and 0.36 g (0.009 mol) of 60% NaH in 50 ml of dry THF were reacted affording 3.8 g of a red oil. Crude was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent to give 2.5 g of a light yellow oil which gas chromatography showed to be 94% pure. This material was passed through a spinning plate preparative chromatograph in two different portions of 1.25 g each (eluting solvent: 40% CH2Cl2 /cyclohexane) to give, after kugelrohr distillation at 105°-125° C./106 Pa, 1.95 g (55%) of product as a clear oil; nD25 1.4831.
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[CH:5][C:4]=1[O:12][CH3:13])=[O:2].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH:1]([C:3]1[C:4]([O:12][CH3:13])=[CH:5][C:6]([O:11][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7][C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1cc(OC)c(C=O)c(OC)c1
Temperature: 110 °C

Procedure:
To a suspension of 4-formyl-3,5-dimethoxyphenol (22.6 9,124 mmol) and potassium tert-butoxide (15.3 g, 136 mmol) in dimethylformamide (125 mL) was added ethyl 5-bromovalerate (28.5 g, 136 mmol) in dimethylformamide (125 mL) over a period of 20 min. The mixture was heated at 110° C. for 6 h and concentrated in vacuo. To the obtained product was added ethyl acetate (400 mL) and the mixture was filtered. The filtrate was washed with water (100 mL), 1 N sodium hydroxide (2×50 mL), and brine (3×100 mL), dried (magnesium sulfate), and concentrated in vacuo to 37 g of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32]([OH:34])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:32](=[O:34])[C:31]3[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=[C:29]([CH3:28])[CH:30]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(C)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 3-methyl-5-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:25][N:15]([CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:16](=[O:24])[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol) in ethanol (35 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (1395 mg, 4.89 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and sodium carbonate (sat) and extracted with dichloromethane. The combine organics were dried, filtered and concentrated, then chromatographed in 1:1 ethyl acetate in hexanes, then ethyl acetate, followed by 5% (2M NH3 in methanol) in 1:1 ethyl acetate dichloromethane, giving the desired phenyl methyl(3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (630 mg, 1.404 mmol, 57.4% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-7.21 (m, 1H), 7.13-7.05 (m, 3H), 6.56 (m, 2H), 6.49 (brs, 1H), 6.25 (brs, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.23-3.19 (m, 2H), 3.06, 2.93 (2s, 3H), 2.69-2.64 (m, 2H), 1.89-1.81 (m, 4H).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31]C5C=CC(OC)=NC4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].[C:42]([O-:45])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:6]5[N:7]=[CH:8][C:9]([O:45][CH3:42])=[CH:10][C:5]4=5)[CH2:24][CH2:25]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cnc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Yield: 23 %

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)carbamate (1.408 g, 2.551 mmol) in chloroform (20 ml) and MeOH (5 ml) was added 4M HCl in 1,4-dioxane (10 ml) and the reaction was stirred at rt for 0.5 h before evaporation, treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound as a yellow solid (266 mg, 23%).