Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:32][CH2:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:33][C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C:51]3=[O:53])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(NC[C@@H]2CCCN2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3CCCN3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.8 %

Procedure:
The starting 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(4-fluoro-2-methylphenyl)-6-{[(2S)-2-pyrrolidinylmethyl]amino}-3-pyridinyl)-N,2-dimethylpropanamide (D62, 38 mg, 0.064 mmol) was dissolved in 1 mL of anhydrous dichloromethane and treated with triethylamine (20 μL, 0.143 mmol). The solution was brought to 0° C. and triphosgene (10 mg, 0.034 mmol) was added. The reaction was stirred at 0° C. for 15 min, then brought to room temperature. After 24 h, the reaction was diluted with dichloromethane (10 mL) and extracted with brine. The organics were collected and the solvent removed. The product was isolated by flash chromatography (silica, cyclohexane:EtOAc 80:20 to EtOAc). Thus were obtained 8 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[NH:30][CH:29]=1)([OH:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO.O>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[C:28]3[CH2:27][C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(B(O)O)cc12
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2ccc3[nH]cc(CC(=O)O)c3c2)n1
Temperature: 130 °C
Yield: 16.9 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (493 mg, 1.408 mmol) and 3-carboxymethyl-1H-indol-5-yl boronic acid (370 mg, 1.689 mmol) in toluene (9 mL), EtOH (4.5 mL) and water (1 mL) is added Cs2CO3 (1.146 g, 3.52 mmol) and degassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (81.3 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 15 minutes. To the reaction mixture is added 1N hydrochloric acid to adjust pH to about 2. This mixture is extracted three times with EtOAc (40 mL). The combined, extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to give (5-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-indol-3-yl)-acetic acid [116 mg, 17%, Example 52] as a solid. LC/MS: RT=2.57 minutes, MS: 489 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □ 12.18 (1H, s), 11.05 (1H, s), 8.18 (1H, s), 7.24-7.76 (7H, m), 6.6 (1H, s), 3.87 (3H, s), 3.7 (2H, s), 3.6 (2H, m), 3 (2H, m). IC50=0.4 nM
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:5]=1[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12])([O-])=O>C(O)C.[Pt].[H][H]>[NH2:1][C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1N

Procedure:
Hydrogenate 3.0 g of 2-(2,4-dinitrobenzylidene)-1-methylpyrrolidine in 50 ml of ethanol with platinum/hydrogen. Filter the catalyst from the hydrogenated product and concentrate the filtrate to obtain the title compound as a yellowish viscous oil which decomposes rapidly in contact with air and under light.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](Br)=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2[C:8]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cc(-c2cnc(N)c3c(Br)csc23)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cnc(N)c3c(-c4ccc(Cl)cc4)csc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 14 h
Yield: 47.8 %

Procedure:
The mixture of 4-amino-3-bromo-7-(3,4,5-trimethoxyphenyl)-thieno[3,2-c]pyridine (30 mg, 0.076 mmol), Pd(PPh3)4 (17 mg, 10 mol %), 4-chlorobenzeneboronic acid (30 mg, 0.19 mmol) and 2M sodium bicarbonate (0.19 ml, 0.38 mmol) in DME (2 ml) was stirred for 14 hours at 80° C. The crude mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH. The eluant was collected and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (15.5 mg) 1H NMR (400 MHz, DMSO-d6) ppm 7.99 (s, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.58 (s, 1H), 7.51 (d, J=7.3 Hz, 2H), 6.95 ((s, 2H), 5.47 (s, 2H), 3.85 (s, 6H), 3.73 (s, 3H). MS: m/z 427, 429 (M+H)+.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[F:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=O.C(#N)C>C1COCC1>[F:17][C:10]([F:9])([F:16])[C:11](=[O:13])[CH2:2][C:3]#[N:5]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a cooled (−78° C.) solution of LDA (2M, 15 g, 39 mmol) in anhydrous THF (50 mL) was added drop-wise a solution of ethyl trifluoroacetate (2.5 g, 18 mmol) and acetonitrile (1.4 g, 35 mmol) in 15 ml THF. The reaction was kept at −78° C. for 45 min, warmed up to room temperature over 1 hour period and quenched with ice water. The reaction was concentrated under vacuum, the residue extracted with ethyl ether, the pH brought to 1 with concentrated HCl, extracted with dichloromethane. The aqueous solution was extracted with ethyl ether, the combined organic layers dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to afford 1.4 g of 4,4,4-trifluoro-3-oxobutanenitrile as a yellow oil, which was used as such in the next step.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11]>>[CH2:1]([O:8][C:14]([NH:13][S:10]([Cl:9])(=[O:12])=[O:11])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)Cl)OCc1ccccc1

Procedure:
The procedure of Example 7 was followed scaling the reaction to 0.2 moles each of benzyl alcohol and chlorosulfonyl isocyanate to give benzyloxycarbonylsulfamoyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:19])[C:10]([S:16]([CH3:18])=[O:17])=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([OH:22])C>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:19])[C:10]([S:16]([CH3:18])(=[O:22])=[O:17])=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(C(C)(C)C)cc21
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(C(C)(C)C)cc21

Procedure:
7-t-butyl-1-methyl-3-methylsulphinyl-4-quinolone was oxidised in chloroform at 20° to give 7-t-butyl-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 247°-248° (from ethanol).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)=O)=CC=1.C[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)[NH:28][CH:29]=[O:30])=[CH:23][CH:22]=1.C(N)=O.B(Br)(Br)Br>C(Cl)Cl>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)[NH:28][CH:29]=[O:30])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(NC=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Solvent: NC=O
Solvent: ClCCl
Product: O=CNC(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Following the procedure in step C of Example 1, 4,4'-dimethoxybenzophenone was converted to N-[bis-(4-methoxyphenyl)methyl]formamide. To a solution of the above formamide (2.2 g, 8.1 mmol) in anhydrous CH2Cl2 (50 ml) at 0° C. under N2 was added 1.0M solution of BBr3 in CH2Cl2 (20.0 ml). After warming to 20° C. and stirring for one hour, the reaction mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The EtOAc fractions were washed with brine, dried over MgSO4 and then stripped to obtain 1.9 g of N-[bis-(4-hydroxyphenyl)methyl]formamide.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[C:47]([F:48])=[C:46](Br)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[C:47]([F:48])=[C:46]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Fc1c(Br)cnn1C1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(Cc5ccccc5)CC4)c3F)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 39 %

Procedure:
XPhos Precatalyst 2nd Generation (6.0 mg, 0.008 mmol) was added to a nitrogen purged solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (30.8 mg, 0.077 mmol), 1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine (26.0 mg, 0.077 mmol), and potassium phosphate (81 mg, 0.384 mmol) in 1,4-dioxane (1.00 mL) and water (0.20 mL), and the reaction mixture was heated at 100° C. overnight. The crude reaction mixture was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 10-20% ethyl acetate in hexanes) to afford methyl (S)-6-(1-(1-benzylpiperidin-4-yl)-5-fluoro-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (16 mg, 39%) as a white solid. MS (ESI, pos. ion) m/z 533 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10](Br)[C:11]#[CH:12]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:12][C:11]#[CH:10]
Reactant: Cc1cccc(C)c1N
Reactant: C#CCBr
Product: C#CCNc1c(C)cccc1C

Procedure:
2,6-Dimethyl-N-propargyl-aniline was prepared by reacting 2,6-dimethyl-aniline with propargyl bromide according to the statements in the literature (see U.S. Pat. No. 4,001,325). ##STR100##
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:7]([CH:8]=O)[C:6]1([CH3:11])[CH3:10])=[O:4].[C:12](#[N:17])[CH2:13][CH:14]=[CH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:7](/[CH:8]=[C:13](\[C:12]#[N:17])/[CH:14]=[CH:15]/[CH3:16])[C:6]1([CH3:11])[CH3:10])=[O:4]
Reactant: CC=CCC#N
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.5 %

Procedure:
Methyl-(1R)-trans-3-formyl-2,2-dimethylcyclopropane carboxylate (2.53 g, 16.2 mmol), 3-pentenonitrile (1.90 g, 23.5 mmol) and anhydrous potassium carbonate (3.22 g, 23.3 mmol) were added to 30 mL of N,N-dimethylformamide and the mixture was stirred at room temperature for 24 hours. The reaction solution was added to 100 mL of ice water and the solution was extracted twice with each 100 mL of ethyl acetate. The obtained ethyl acetate layers were combined, washed once with 50 mL of saturated brine and then dried over magnesium sulfate. After concentration under reduced pressure condition, the residue was subjected to silica gel column chromatography to obtain 0.94 g of methyl-(1R)-trans-3-[(1Z,3E)-2-cyano-1,3-pentadienyl]-2,2-dimethylcyclopropane carboxylate represented by the following formula:
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:20])C(=O)C1>CC#N>[Cl:20][C:5]1[C:6]([C:9]([F:11])([F:12])[F:10])=[N:7][NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCc1cc(C(F)(F)F)n[nH]1
Solvent: CC#N
Product: CCCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-propyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[CH:23][C:12]3[C@:13]4([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=3[CH:10]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[CH:5][CH:4]=1)#[N:2].[CH2:25](O)CCC.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C#N)cc3)ccc12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C#N)cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (24 mg, 0.08 mmol), 0.20 mL of n-butanol, and potassium t-butoxide (26 mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography ethyl acetate eluent) to give 20 mg (80%) of the title compound as a white solid. mp 148°-150°. FDMS: m/e=330.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:2]3=[O:1])=[O:16])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CCCNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-2-oxo-1-[(propylamino)carbonyl]-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 502 (M++1). 1H NMR (CD3OD) δ 0.95 (t, 3H), 1.55 (m, 4H), 1.90 (m, 3H), 2.10 (d, 1H), 3.10 (m, 4H), 3.25 (m, 3H), 3.65 (m, 4H), 4.80–4.95 (m, 4H), 5.86 (d, 1H), 6.12 (s, 1H), 7.12 (d, 1H), 7.58 (s, 1H), 7.65 (d, 1H), 9.00 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][C:7]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[OH:1][CH2:2][CH:3]([CH3:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][C:7]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
A solution was prepared by dissolving 34.1 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1. A reaction mixture solution prepared by adding 0.2 mL of 2 M sodium hydroxide aqueous solution to the solution was stirred at room temperature for 3 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic layer was concentrated, followed by purifying by a conventional method to obtain 15.4 mg of 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]([CH3:25])([CH3:24])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH:12]([OH:22])[CH2:13][C:14]([CH:16]1[CH2:21][O:20][C:18](=[O:19])[CH2:17]1)=[O:15]>CCOCC>[OH:22]/[C:12](/[CH2:11][CH:10]([CH3:23])[CH2:9][CH2:8][CH2:7][C:6]([O:5][CH3:4])([CH3:24])[CH3:25])=[CH:13]/[C:14](=[C:16]1[CH2:21][O:20][C:18](=[O:19])[CH2:17]1)[O:15][CH3:3]
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(/C=C(/O)CC(C)CCCC(C)(C)OC)=C1COC(=O)C1
Reaction time: 4 h
Yield: 61.3 %

Procedure:
An etherealdiazomethane solution containing 0.04 moles of diazomethane is added to a solution of 2.0 g (0.006 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 5 ml of dry ether, and the reaction mixture is allowed to stand at room temperature for 4 hours. The solvent is distilled off in vacuo, the residue is taken up with ether, and the solution is filtered through a short column filled with Kieselgel 60 adsorbent. Ether is removed from the effluent to obtain 1.2 g (63.2%) of the aimed compound as a pale yellow oil; Rf =0.62 (developed with a 10:0.4 mixture of benzene and methanol).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)(C(C)(C)C)(C)C.[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([CH:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[CH:26]=1
Reactant: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (1.01 g, 2.37 mmol) in CH2Cl2 (10 mL) at 0° C. was added 4 M HCl in dioxane (5.93 mL, 23.7 mmol). The resulting mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was triturated with ether. The resulting solids were filtered and dried under reduced pressure to afford (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.577 g, 2.33 mmol, 98.2% yield). MS (APCI) m/z=212.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](I)[CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: CCCCCI
Reactant: N#Cc1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1ncc(C#N)c1N
Temperature: 80 °C
Reaction time: 0.16 h

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 15 g, 0.138 mol), pentyliodide (Acros, 24.45 ml, 0.187 mol) and anhydrous potassium carbonate (Fisher, 25.88 g, 0.187 mol) were suspended in 100 mL anhydrous DMF and heated at 80° C. under nitrogen overnight. HPLC analysis (Method D) showed starting material still present. An additional 9 ml (69 mmol) of pethyliodide and 9.5 g (69 mmol) K2CO3 were added to the reaction and heating continued for 5 more hours. The reaction was permitted to cool and the DMF was removed on a rotary evaporator. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded orange solid which contained both pentyl isomers and residual DMF by NMR analysis (27.65 g, greater than theoretical yield). This was carried on crude. HPLC (1 peak, 63%) elutes at 9.5 minutes (Method D). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 (s, 1H), 6.15 (s, 1H), 5.33 (s, 2H), 3.80 (t, J=7, 2H), 1.68 (m, 2H), 1.25 (m, 4H) 0.75 (t, J=7, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Br:11])[CH:5]=1.[Br-].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([Zn+])=[N:19][CH:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][N:19]=2)[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: Cc1ccc([Zn+])nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution methyl-3-bromo-5-iodobenzoate (10.0 g, 29.3 mmol) and 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 64.5 mL, 32.3 mmol) in tetrahydrofuran (84 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.70 g, 1.47 mmol). The reaction mixture was stirred at ambient temperature. After 6 h, saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with sodium potassium tartrate tetrahydrate (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/ethyl acetate) gave the title compound. MS 306.0 (M).