Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[I:17]I.Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:17])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of 26 g 3-Hydroxybenzoic acid and 43 g Na2CO3 in 45 mg H2O at 100° C. was added dropwise a solution of 48 g KI and 48 g iodine in 135 ml H2O. After heating for additional 3 h the mixture was cooled to RT and acidified with concentrated HCl. The title compound precipitated as a white solid and was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1I
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3I)c2)CC1
Yield: 15.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-iodobenzoyl chloride (183 mg, 0.687 mmol), 16.0 mg (16%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.3, 100 mg, 0.264 mmol), (R)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. The RM was diluted with TBME/EtOAc (1:1) (30 mL), washed with 0.5 M HCl (3×5 mL) and brine (5 mL) and the solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.83 min, m/z=444.9/446.9 [M+H]+, m/z=443.0/445.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.92 (m, 1H) 1.92-2.04 (m, 1H) 3.24-3.30 (m, 1H). 3.36-3.46 (m, 1H) 3.60-3.72 (m, 1H) 3.81 (dd, J=10.51, 4.65 Hz, 1H) 4.36 (d, J=2.69 Hz, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.90 (m, 3H) 8.14 (d, J=1.96 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [Si]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)(C(C)(C)C)(C)C.[NH2:19][C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[OH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:19][C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1)=[O:12]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reactant: Cc1cnc(N)cn1
Product: CCCCC(O)C(=O)Nc1cnc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate and 2-amino-5-methylpyrazine, 1H NMR (300 MHz, CDCl3) δ 9.46 (s, 1H), 8.98 (br s, 1H), 8.12 (s, 1H), 4.32 (m, 1H), 2.98 (d, 1H), 2.54 (s, 3H), 1.96 (m, 1H), 1.78 (m, 1H), 1.44 (m, 4H), 0.93 (t, 3H).
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.C(O)(=O)C.Cl.[C:23]([NH:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([N:27]1[C:5]2[C:4](=[O:3])[CH2:9][CH2:8][CH2:7][C:6]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nn(C(C)(C)C)c2c1CCCC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 10 g (42.6 mmol) and acetic acid 5 ml in absolute ethanol (150 ml) at room temperature was added tert-butyl hydrazine hydrochloride 6 g (48 mmol). The mixture was stirred at 60° C. for 3 hours. The volatiles were removed under vacuum, the residue was diluted with DCM and washed with sat. aqueous solution of NaHCO3, and with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1:2) to give ethyl 1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 90% yield. LC/MS (254 nm) HPLC method 2 Rt 6.08 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.18 (q, J=6.83 Hz, 2H) 2.93-2.30 (3 m, 6H) 1.58 (s, 9H), 1.16 (t, J=6.83 Hz, 3H). HRMS (ESI) calcd for C14H20N2O3 [M+H]+ 287.1366 found 287.1356.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[CH2:2][CH3:3].[Li]CCCC.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>C1COCC1>[CH2:1]([N:4]1[C:8]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:7][CH:6]=[N:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cccn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the above THF solution of 1-propyl-1H-pyrazole was added n-BuLi (2.5M in Hexane, 40 mL, 100 mmol) at −78° C. The reaction solution was stirred for 2 hours at RT and then re-cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.6 g, 100 mmol). After 30 min at −78° C., the reaction was quenched with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid which was used directly without further purification: LC-MS (ES) m/z 154 (M+H)+ for [RB(OH)2].
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=1.[CH3:16]C1NNC(=O)C=1.BrCCCC1C=CC=CC=1>>[CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][C:10]2[CH:16]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1
Reactant: CCCCCCCCN1N=C(C)CC1=O
Reactant: Cc1cc(=O)[nH][nH]1
Agent: BrCCCc1ccccc1
Product: CC1=NN(CCCc2ccccc2)C(=O)C1
Yield: 69 %

Procedure:
By a procedure similar to that for 2,4-dihydro-5-methyl-2-octyl-3H-pyrazol-3-one, starting from 3-methyl-3-pyrazoline-5-one (19.63 g, 0.20 mol) and 1-bromo-3-phenylpropane (39.80 g, 0.20 mol), 2,4-dihydro-5-methyl-2-(3-phenylpropyl)-3H-pyrazol-3-one (29.40 g, 69%) was obtained as colorless needles, m.p. 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[C:11]([F:16])[CH:10]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2cc(F)nc(F)c2)c1-c1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanone (60 mg, 0.2 mmol), ammonium acetate (130 mg, 1.7 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C20H15ClF2N (M−NH2)+: m/z=342.1. found: 342.1.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.59 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.36 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.14-7.11 (m, 3H), 7.08-7.04 (m, 2H), 6.91 (t, 1H, J=7.43 Hz), 6.82-6.77 (m, 3H), 4.15 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.94 (t, 2H, J=6.65 Hz), 2.33 (s, 3H), 2.17 (s, 3H, 1.48 (s, 3H). MS [ES+] m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1676.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].I[CH2:30][CH3:31]>>[CH2:30]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:12]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])=[N:13]1)[CH3:31]
Reactant: CCOc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCOc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 4-[(4-ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1([C:14]2([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]2)[CH2:13][O:12]1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:14]1([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]1)([OH:12])[CH2:13][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSC1(C(O)(/C=C/c2ccc(Cl)cc2Cl)Cn2cncn2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
A solution of 38.2 g (0.12 mol) of 2-(2,4-dichlorophenyl-ethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane in 30 ml of dimethylformamide is added dropwise at 80° C. under a nitrogen atomsphere and with stirring to a mixture of 24 g (0.35 mol) of 1,2,4-triazole, 2.7 g (0.02 mol) of potassium tert.-butylate and 50 ml of dimethylformamide. The mixture is stirred for 6 hours at 80° C., then the solvent is stripped off under reduced pressure, and the residue is taken up in ethyl actate/toluene, washed using water, dried over sodium sulphate and concentrated under reduced pressure. The residue remaining is chromatographed on silica gel using chloroform as eluant. In this manner, 12.1 g (26% of theory) of trans-4-(2,4-dichlorophenyl)-2-(1-propylmercaptocyclopropyl)-1-(1,2,4-triazol-1-yl)-but-3-en-2-ol are obtained in the form of an oily product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([NH:54][C:55]2[C:56](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:57](O)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:57](=[O:58])[C:56]3[CH:60]=[CH:61][CH:62]=[CH:63][C:55]=3[NH:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with N-phenylanthranilic acid (21 mg) and N,N-diisopropylethylamine (33 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][NH:10][C:9]2=O.CN(C)C=O.C(Cl)(=O)C([Cl:30])=O.O>ClCCl>[Cl:30][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 126.7 %

Procedure:
To a solution of compound 22 (2.60 g, 8.83 mmol) in dichloromethane (25 mL), was added a drop of N,N-Dimethyl formamide and to that oxalyl chloride (1.52 mL, 17.669 mmol) was added dropwise. This mixture was stirred at room temperature for 12 h. Reaction was monitored by TLC and the reduction continued until TLC indicated no starting material. The reaction mixture was poured in to water. Extracted with ethyl acetate and the combined organic layer were washed with Sat.NaHCO3 and brine and dried over Na2SO4 and evaporated to give the crude compound 23 (3.5 g, crude), which was used in the next reaction without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22]C1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.IC.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Solvent: CI
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (72%) as a white solid: mp 142-144° C.; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][CH:3]([CH2:7][O:8][C:9]1[C:17]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([F:21])[CH:10]=1)[CH2:2]2.CS(N)(=O)=O.[N:27]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1>>[N:27]1([S:31]([NH:34][C:13](=[O:14])[C:12]2[CH:16]=[C:17]([CH:18]3[CH2:19][CH2:20]3)[C:9]([O:8][CH2:7][CH:3]3[CH2:4][CH:5]4[CH:1]([CH2:6]4)[CH2:2]3)=[CH:10][C:11]=2[F:21])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F
Agent: CS(N)(=O)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white solid (0.037 g, 27%): 1H NMR (300 MHz, CDCl3) δ11.60 (br, s, 1H), 7.13 (d, J=8.31 Hz, 1H), 6.94 (d, J=12.98 Hz, 1H), 4.11-3.96 (m, 4H), 3.83 (d, J=7.42 Hz, 2H), 2.83-2.67 (m, 1H), 2.25-2.07 (m, 4H), 2.05-1.92 (m, 1H), 1.58-1.45 (m, 2H), 1.37-1.26 (m, 2H), 0.94-0.82 (m, 2H), 0.72-0.54 (m, 3H), 0.14-0.06 (m, 1H); MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]#[N:11]
Reactant: ClCc1ccccn1
Reactant: COc1ccccc1CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)Cc1ccccn1

Procedure:
This intermediate (80 g.) was prepared using the procedure described in Example 14a except using 50 g. (0.339 mole) of (2-methoxyphenyl)acetonitrile, 56 g. (0.339 mole) of 2-(chloromethyl)pyridine hydrochloride, 60 g. (0.746 mole) of 50% aqueous sodium hydroxide, and 200 ml. of DMSO.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:11]2[N:12]([CH3:17])[C:13](=[S:16])[NH:14][N:15]=2)[CH:7]=[C:8]([F:10])[CH:9]=1.[OH-].[Na+]>CC(C)=O.O>[F:10][C:8]1[CH:7]=[C:6]([C:11]2[N:12]([CH3:17])[C:13]([S:16][CH3:1])=[N:14][N:15]=2)[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSc1nnc(-c2cc(F)cc(F)c2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
MeI (1.4 mL, 22.4 mmol) was added to a mixture of 5-(3,5-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5 g, 22 mmol) in acetone (80 mL). NaOH (0.9 g, 22 mmol) in H2O (20 mL) was added and the reaction was stirred for 3 h at r.t. The formed precipitate was filtered off and the solution is evaporated to half volume and the formed precipitate was filtered off and combined with the first filtrate to give 4.92 g (93%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[C:9]=2[C:25]#[N:26])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[C:25]([C:9]1[C:10]([O:17][S:18]([C:21]([F:23])([F:24])[F:22])(=[O:20])=[O:19])=[N:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:36])=[CH:7][CH:6]=1)#[N:26]
Reactant: O=C=Nc1ccccc1F
Reactant: N#Cc1c(-c2ccc(N)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Product: N#Cc1c(-c2ccc(NC(=O)Nc3ccccc3F)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Yield: 66 %

Procedure:
In analogy to GP 4, reaction of 200 mg trifluoromethanesulphonic acid 4-(4-amino-phenyl)-3-cyano-6-cyclopropyl-pyridin-2-yl ester (0.522 mmol) and 71 μl 1-fluoro-2-isocyanato-benzene yielded 179 mg product (0.343 mmol, 66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[C:15]([CH:20]([CH3:24])[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21](=[O:22])[CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]=[CH:10]3)[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Br)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Br)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 371, 369 (M+H)+; MS (ESI−) m/z 369, 367 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.23 (d, J 6.1, 2H), 4.63 (q, J 7.1, 1H), 7.14 (m, 2H), 7.47 (m, 2H), 7.76 (m, 1H), 7.98 (t, J 7.5, 1H), 8.17 (d, J 7.1, 1H), 8.43 (d, J 7.8, 1H), 8.69 (br s, 1H), 8.74 (d, J 6.8, 1H), 8.92 (t, J 5.8, 1H), 9.88 (s, 1H); Anal. Calcd for C19H17BrN2O+1.4 HCl: C, 54.30; H, 4.41; N, 6.66. Found: C, 54.49; H, 4.28; N, 6.75.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([CH2:13][N:12]2[C:3]3=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:16][CH2:15]1
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1cnc(NCC2CC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Yield: 33.7 %

Procedure:
Following general procedure 13B: Combined methyl 5-amino-6-[(cyclopropylmethyl)amino]nicotinate (950 mg, 4.3 mmol), DIPEA (1.1 ml), 4-ethoxyphenylacetic acid (850 mg, 4.72 mmol) and HATU (1.80, 4.74 mmol) in DMF (15 mL). The crude product was purified by flash chromatography on silica gel (EtOAc) to produce the desired product (530 mg, 34%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([O:13][CH:14]([C:19]2(F)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]([F:18])([F:17])[F:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].[C:38](=O)(O)[O-].[Na+]>ClCCl>[Cl:2][C:3]1[C:12]([O:13][CH:14]([C:19]2([CH3:38])[CH2:24][CH2:23][N:22]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:21][CH2:20]2)[C:15]([F:18])([F:17])[F:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)C1(F)CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(Oc2nc3ccccc3nc2Cl)C(F)(F)F)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-Chloro-3-[2,2,2-trifluoro-1-(4-fluoropiperidin-4-yl)-ethoxy]quinoxaline hydrochloride (157 mg, 0.396 mmol) was dissolved in dichloromethane (3.0 mL). To this, triethylamine (0.197 mL, 1.19 mmol) and methanesulfonyl chloride (0.0459 mL, 0.594 mmol) were successively added and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give Compound BAI (146 mg, yield: 84%).