Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 77 %

Procedure:
Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 130 mg (77%) of product as a colorless hard foam.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH3:19][N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1>>[CH3:19][N:20]1[C:24]([NH:25][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[CH:23][CH:22]=[N:21]1
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: Cn1nccc1N
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3ccnn3C)c2o1
Yield: 33.3 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.23 g) and 2-methyl-2H-pyrazol-3-ylamine (0.1 g). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane afforded the title compound as a cream solid (0.10 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([N+:17]([O-])=O)[CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)(=[O:4])=[O:3].[H][H].[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>[Pd].C(O)C>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:17][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)Nc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Reactant: [H][H]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cc(NS(C)(=O)=O)cc(NS(C)(=O)=O)c2)C(=O)OC1=O

Procedure:
A mixture of 1.5 g. (0.005 mol) of 3,5-bis-methylsulfonamidonitrobenzene in 100 ml. of ethanol and 300 mg. of 10% palladium-on-carbon was hydrogenated in a Parr apparatus until hydrogen uptake had ceased. The catalyst was filtered, the ethanol was removed under reduced pressure and the residue was dissolved in 30 ml. of methanol. This solution of 3,5-bis-methylsulfonamidoaniline (1.36 g.) and 1.06 g. (0.005 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one was refluxed for two hours under nitrogen. The reaction mixture was filtered to give 5-acetyl-4-hydroxy-3-[1-(3,5-bis-methylsulfonamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[O:24][CH2:25][CH3:26])[CH:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([NH:35][S:36]([C:39]1[S:40][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:43]=1)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][S:36]([C:39]1[S:40][C:41]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:27]([F:28])([F:29])[F:30])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=4[O:24][CH2:25][CH3:26])[N:13]=3)[CH:3]=2)=[CH:42][CH:43]=1)(=[O:37])=[O:38])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CCOc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Product: CCOc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(2-ethoxy-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromophenyl)-4-(2-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.108) (0.185 g, 0.41 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (example F.1) (0.17 g, 0.49 mmol) according to the general procedure VI. Obtained as an off-white foam (0.18 g), which was subsequently deprotected.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11]2)C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2-].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38]>CCOCC.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38].[CH:7]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CN1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)CN1CCC(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of 41.3 g. (0.13 mole) of α,α-diphenyl-α-(1-isobutyl-3-pyrrolidinyl)acetonitrile in 120 ml. of dry toluene was added 11.2 g. (0.286 mole) of sodium amide in a 500 ml. round bottom flask equipped with a reflux condenser and mechanical stirrer. The stirred mixture was refluxed for 46 hours. A large excess of water was added slowly and the water layer separated and discarded after being extracted with ether which was combined with the organic layer. The organic layer was washed with water and extracted with an excess of 2 N hydrochloric acid. The acid extract was basified with sodium hydroxide and the oil which separated was extracted with ether. The ethereal solutions were combined, concentrated and the residue was distilled. Yield, 25.8 g. (68%); b.p. 150°-152° C/0.05 mm. To 11.2 g. (0.0382 mole) of the above product was added 4.45 g. (0.0382 mole) of maleic acid in 150 ml. of absolute alcohol. After the amine dissolved, 100 ml. of dry ether was added. On standing in the refrigerator for several days the solution yielded a white solid which was recrystallized from ethyl acetate. Yield, 10.5 g. (67.25%); m.p. 119°-120° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C:41]#[CH:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:39][CH2:40][C:41]#[CH:42])=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C#CCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: C#CCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.9 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]>O1CCCC1.C(OCC)(=O)C>[N+:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[NH:4][CH2:3][CH2:1][OH:2])([O-:14])=[O:13]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A mixture of ethanol amine (5.96 mL, 49.4 mmol) and 2-chloro-1,3-dinitrobenzene (5.00 g, 24.7 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid (5.54 g, 24.4 mmol, 99%).
Reaction SMILES: [C:1](Cl)(=[O:28])[O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=[O:27])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1F.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.CO>[N:30]1([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/2=[N:14]\[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[N:30]2[CH2:33][CH2:32][CH2:31]2)=[O:28])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: C1CNC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cn(CCOC(=O)N2CCC2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2N2CCC2)s1
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of Example 61B (174 mg, 0.384 mmol) in CH2Cl2 (1.4 mL) was added azetidine (110 mg, 1.920 mmol) in methanol (0.5 mL) and the mixture was stirred for 2 hr. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (38 mg, 0.074 mmol, 19.38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (m, 9 H) 1.99-2.12 (m, 2 H) 2.18-2.29 (m, 2 H) 3.78 (t, J=7.29 Hz, 4 H) 3.87 (t, J=7.46 Hz, 4 H) 4.35 (dd, J=14.24, 4.75 Hz, 4 H) 6.57 (d, J=8.82 Hz, 1 H) 7.27 (s, 1 H) 7.51 (dd, J=8.65, 1.86 Hz, 1 H) 7.87 (d, J=1.70 Hz, 1 H); MS (DCI) m/z 511 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([OH:23])[CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1)[O:23][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:33])=[O:34])=[CH:28][CH:27]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.12 mmol) synthesized in Example (116d) and 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine (25 mg, 0.15 mmol) synthesized in Example (116a) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (51 mg, 0.37 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. 1-[(4-Fluorophenyl)sulfonyl]-4-methylpiperazine (30 mg) was added again, and the mixture was stirred at 90° C. overnight. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (25 mg, yield 35%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(Br)cc1
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 14 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.28 g (25 mmols) of 4-bromotoluene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 23 hours at 130° C., 0.67 g (3.5 mmols) of ethyl 4-methylcinnamate is obtained, corresponding to a yield of 14% of theory (conversion figure 1400; Pd content 0.01 mol %).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:8]1[C:19](OCC)=[O:20])([CH3:4])[CH3:3].OC[C@@H]1[C@@H](C)CCN1C(OC(C)(C)C)=O>>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C@@H:8]1[CH2:19][OH:20])([CH3:1])[CH3:3]
Reactant: CCOC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO

Procedure:
The title compound was prepared from 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate using the methods used for preparation of 1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate. 1H NMR (400 MHz, DMSO-D6) δ ppm −0.0 (m, 6H), 0.8 (m, 9H), 1.0 (m, 1H), 1.4 (m, 9H), 1.6 (m, 1H), 3.1 (m, 1H), 3.2 (m, 2H), 3.5 (m, 2H), 4.3 (m, 1H), 4.8 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17](O)=[O:18]>>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][CH:17]=[O:18])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
A mixture of 100 g (0.43 mole) of 2-amino-5-chlorobenzophenone and 500 g formic acid was refluxed for 1 hr, and then cooled and poured into 1 l. of ice water. The solid that precipitated was collected on a filter, washed with water, dried in air, and recrystallized from heptane-benzene to give 103.5 g (93%) of the formamide as colorless crystals, mp 89°-91°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([OH:31])=O)[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:31])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)CCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)O)c4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid (Example 123) (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another 10 minutes, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate as off-white solid. Yield: 115 mg, 97%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:4]1=[O:17].[Cl:18]C1C=CC(B(O)O)=CC=1>>[ClH:16].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)[C:4]1=[O:17]
Reactant: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl
Product: N[C@H]1CCCCN(c2ccc(Cl)cc2)C1=O

Procedure:
(S)-3-Amino-1-(4-chlorophenyl)azepan-2-one hydrochloride (35 mg, 0.127 mmol) was synthesized as described for the preparation of Intermediate 49 using 4-chlorophenylboronic acid in step A. Anal. Calcd. for C12H15ClN2O m/z 238.8. found: 239.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@@H:17]3[CH2:20][C@H:19]([N:21]([CH3:23])[CH3:22])[CH2:18]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:24]([O:31]C1C=C(C2N=C(C3CC(=O)C3)N3C=CN=C(Cl)C=23)C=CC=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C[NH:54]C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CC(O)=O.ClCCCl>[CH2:24]([O:31][C:13]1[CH:12]=[C:11]([C:10]2[N:9]=[C:8]([C@H:17]3[CH2:20][C@@H:19]([N:21]([CH3:23])[CH3:22])[CH2:18]3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:54])[C:3]=23)[CH:16]=[CH:15][CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)[C@H]1C[C@@H](c2nc(-c3ccccc3)c3c(Cl)nccn32)C1
Reactant: CNC
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-[3-(8-Chloro-1-phenyl-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-dimethyl-amine: An DCE solution of 3-{1-[3-(benzyloxy)phenyl]-8-chloroimidazo[1,5-a]pyrazin-3-yl}cyclobutanone was charged with dimethylamine (0.37 mmol, 0.19 mL) and then catalytic amount of AcOH (7 μL). The mixture was stirred at rt for 30 min before resin-bound triacetoxyborohydride (0.5 mmol, 240 mg) was added. Reaction mixture was stirred at rt for 16 h before the solution was filtered through a Buchner funnel to remove the resin. The filtrate was concentrated and the obtained oil was dissolved in DCM (15 mL), washed with saturated NaHCO3 solution (2×15 mL) and brine (2×15 mL). The solvent was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a yellow greasy oil; MS (ES+): m/z 433 (100) [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:28][C:29]1[CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=[CH:33][C:34]=1F>CN(C=O)C.CC#N>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:34]3[CH:33]=[CH:32][C:31]([N+:36]([O-:38])=[O:37])=[CH:30][C:29]=3[F:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 7-(benzyloxy)-6-methoxyquinolin-4(1H)-one (4.4 g, 15.6 mmol), Cs2CO3 (9.0 g) in DMF (40 mL) and CH3CN (40 mL) was stirred for 30 minutes at rt. To this mixture was added 3,4-difluoronitrobenzene (2.5 g, 15.7 mmol), and the reaction mixture was stirred at rt overnight. The reaction product was a mixture of O- and N-alkylation products. It was mostly concentrated in vacuo, EtOAc (200 mL) and water (50 mL) were added to the residue, EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexane:EtOAc:MeOH/800:200:40, and then 700:300:40 to obtain the desired O-alkylation product (3.0 mg, 46%) as a white solid. 1H NMR (CDCl3) δ 8.73 (d, 1H, J=6.0 Hz), 8.29-8.26 (m, 2H), 8.08 (s, 1H), 7.60-7.35 (m, 7H), 6.67 (d, 1H, J=6.6 Hz), 5.42 (s, 2H), 4.10 (s, 3H); MS(ESI+) m/z 421.3 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:35][N:34]=[CH:33][C:32]=2[F:36])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>CC(O)C.CCOC(C)=O>[F:36][C:32]1[CH:33]=[N:34][NH:35][C:31]=1[C:30]1[C:11]([N:37]2[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=[O:16]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Reactant: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1
Temperature: 140 °C

Procedure:
DIPEA (71.9 μL, 0.412 mmol) was added to a solution of 6-chloro-5-(4-fluoro-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 5.1, 75 mg, 0.187 mmol) and (R)-pyrrolidin-3-ol (19.97 mg, 0.225 mmol) in iPrOH (187 μL) in a vial which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a white foam. HPLC (Condition 4) tR=4.73 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=452.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.95 (m, 2H) 3.00 (d, J=11.34 Hz, 1H) 3.18-3.51 (m, 3H) 4.22 (br. s, 1H) 4.86 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.77-8.11 (m, 4H) 8.76 (br. s, 1H) 10.17 (s, 1H) 12.90 (br. s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C@@H:11]([C:16]([OH:18])=[O:17])[NH:12][CH2:13]2)=[CH:8][CH:7]=1.[CH3:19]O>>[ClH:3].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C@@H:11]([C:16]([O:18][CH3:19])=[O:17])[NH:12][CH2:13]2)=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Thionyl chloride (1.629, 13.6 mmol) was added dropwise to a solution of (3S)-7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (0.75 g, 3.9 mmol) in methanol (30 mL) at about 0° C. under N2. The solution was warmed to about 25° C. and stirred for about 6 h, then was concentrated. The residue was washed with ether, followed by 1:1 ether pentane and dried under vacuum to yield 0.85 g of product as a white solid (89% yield). 1H NMR (d6DMSO) δ 3.09 (m, 2H); 3.78 (s, 3H); 4.23 (apparent s, 2H); 4.51 (m, 1H); 6.61 (s, 1H); 6.72 (d, J=3 Hz, 1H); 7.04 (d, J=3 Hz, 1H).