Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1ccccc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (1.0 g, 5.4 mmol) and 2-amino-N-methylbenzamide (0.98 g, 6.5 mmol) in THF (5.0 mL) was charged with DIPEA (1.42 mL, 8.18 mmol) and the mixture allowed to stir at rt for 16 h. The reaction was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL), dried over NaSO4, filtered, and concentrated in vacuo to yield a yellow solid which was recrystallized from EtOAc to afford 422 mg of 2-[(2,5-dichloropyrimidin-4-yl)amino]-N-methylbenzamide (yield: 26% yield*). Further material could be recovered from the mother liquors if desired. 1H NMR (CD3OD, 400 MHz): δ=2.93 (s, 3 H), 7.21 (td, J=7.64, 1.14 Hz, 1 H), 7.56 (ddd, J=8.53, 7.26, 1.64 Hz, 1 H), 7.71 (dd, J=7.83, 1.26 Hz, 1 H), 8.30 (s, 1 H) 8.63 (dd, J=8.59, 0.76 Hz, 1 H). MS (ES+): m/z 296.90 [MH+] (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=1.[N:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[CH2:15][CH2:16][C:11]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[N:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])[N:20]=[N:21][N:10]=3)[CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:12][CH2:13]1
Reactant: CC1(C)CC=C(c2cc(CC#N)ccc2N)CC1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2cc(Cc3nnnn3[Sn](C)(C)C)ccc2N)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of [4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-acetonitrile (as prepared in the previous step, 417 mg, 1.73 mmol) and azidotrimethylstannane (428 mg, 2.08 mmol) in toluene (8 mL) was heated at reflux for 40 h. The reaction was allowed to cool to room temperature and then filtered. The precipitate was washed with 20 mL of toluene and dried under vacuum to afford 410 mg (53%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H21N5, 284.1 (M-SnMe3+2H), found 284.1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:26]([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:23][CH2:30][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Reactant: CC(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CCOc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Yield: 80.3 %

Procedure:
2-Benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (1.1 g, 3.5 mmol) and 2-bromopropionic acid (1.2 g, 7.8 mmol) were reacted in acetone (300 mL) in presence of potassium carbonate (2.3 g, 5.1 mmol) and potassium iodide (0.1 g, 0.6 mmol), following the procedure of Example 22 to give 1.1 g of 2-benzyloxy-5-(2-carboxy-ethoxy)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-(2-carboxy-ethoxy)-benzo[de]isoquinoline-1,3-dione (1.1 g) in the presence of 10% Pd/C (0.5 g) in DMA (20 mL) afforded 0.3 g of the title compound, mp 236-239° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]2[N:6]([C:8]([C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I:33]I>O1CCCC1.S(=O)(O)[O-].[Na+].[Cl-].N>[F:1][C:2]1[C:3]([I:33])=[C:4]([F:22])[C:5]2[N:6]([C:8]([C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nnc2c(F)cc(F)cn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: O=S([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)c1nnc2c(F)c(I)c(F)cn12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 52.8 %

Procedure:
To a solution of tert-butyl [1-(6,8-difluoro[1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-methylethyl]carbamate (1.32 g, 4.23 mmol) in tetrahydrofuran (20 mL) under argon atmosphere and at −78° C. was slowly added LiHMDS (1M in hexanes, 9.3 mL, 9.3 mmol). It was stirred at −78° C. for 45 min, afterwards a solution of iodine (1.13 g, 4.44 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 2 hours, warmed to 0° C. and diluted with aqueous sodium bisulphite (10 mL) and saturated ammonia chloride (10 mL). It was warmed to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified by silica flash chromatography eluting with hexanes/ethyl acetate, using a gradient from 50% to 83% of ethyl acetate to yield the title compound (0.979 g, 53%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=O)[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:15])[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Aqueous NaOH (1.11 g, 27.88 mmol) was added to a solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 18.58 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and dried under reduced pressure to obtain corresponding acid. The crude acid (4.4 g, 18.2 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.55 g, 36.51 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYB OP (14.24 g, 27.38 mmol) was added to it and stifling was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain a solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (4 g, 58.5%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:40])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[C:29]5[CH2:37][CH:36]([CH3:38])[NH:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:35]1[CH:36]([CH3:38])[CH2:37][C:29]2[C:28]([O:27][C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([C:16](=[O:17])[NH:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:7])([F:39])[F:40])[CH:10]=3)[CH:19]=[CH:20]4)=[N:33][CH:32]=[N:31][C:30]=2[CH2:34]1
Reactant: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1
Reactant: COC(=O)CBr
Solvent: CC#N
Product: COC(=O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2CC1C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.15 mL, 1.58 mmol) is added to a solution of 5-(6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 52-B, (0.370 g, 0.792 mmol) and TEA (0.44 mL, 3.17 mmol) in ACN (10 mL). The solution is allowed to stir overnight. The solution is then concentrated and the residue separated directly via FCC (30-100% EtOAc/heptane) to give {6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid methyl ester.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[O:10])[NH:8][CH:9]=1.I[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>C(O)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7](=[O:10])[NH:8][CH:9]=1
Reactant: COCCCI
Reactant: O=c1[nH]cc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCCCOc1cc(Br)c[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a 1.4M NaOH solution at 0° C. are added 0.9 mol 5-bromo-3-hydroxy-1H-pyridin-2-one [34206-49-0]. The mixture is allowed to stir for 15 minutes and 0.9 mmol 1-iodo-3-methoxypropane [61542-10-7] are added carefully at 0° C. The mixture is stirred at room temperature for 3 hours, then neutralized with acetic acid to pH 7. The mixture is extracted with chloroform (10×) and the organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([F:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(O)=O.O>CN(C)C=O.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.C(OCC)(=O)C>[F:17][C:9]1[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCC2)c(F)c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 1.7 g of methyl 2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 15 mL of N,N-dimethylformamide, 0.38 g of tetrakis(triphenylphosphine)palladium(0) and 1.4 mL of triethylamine were added at room temperature, and 0.37 mL of formic acid was dropped thereto. The mixture was stirred at 80 to 90° C. for 2 hours 30 minutes under a nitrogen atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution. To the organic layer, a mixed solvent of chloroform:methanol was added, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, a mixed solvent of diethyl ether:ethyl acetate (1:2) was added, the insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using an eluent of chloroform to obtain 1.3 g of methyl 5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a light yellow solid.
Reaction SMILES: N1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([C:21]4[O:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:24][N:25]=4)[C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:10][CH:9]=2)(=[O:7])=O)CCC1.[C:32]1(C2OC(C3C(N)=NC=C(C4C=CC=CC=4C4C=CC=CC=4)N=3)=NN=2)[CH:37]=CC=C[CH:33]=1.C(SC1C=CC=CC=1C1N=C(C2OC(C3C=CC=CC=3)=NN=2)C(N)=NC=1)C.O1C(C2C=CC=CC=2C2N=C(C3OC(C4C=CC=CC=4)=NN=3)C(N)=NC=2)=CN=C1.C(S(C1C=CC=CC=1C1N=C(C2OC(C3C=CC=CC=3)=NN=2)C(N)=NC=1)(=O)=O)(C)C>>[CH:32]([S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)[C:17]([NH2:20])=[N:18][CH:19]=2)=[CH:12][CH:13]=1)=[O:7])([CH3:37])[CH3:33]
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)N3CCC3)cc2)nc1-c1nnc(-c2ccccc2)o1
Reactant: Nc1ncc(-c2ccccc2-c2ccccc2)nc1-c1nnc(-c2ccccc2)o1
Agent: CC(C)S(=O)(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Agent: CCSc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Agent: Nc1ncc(-c2ccccc2-c2cnco2)nc1-c1nnc(-c2ccccc2)o1
Product: CC(C)S(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)cc1

Procedure:
Compound IA-112 5-[4-(azetidin-1-ylsulfonyl)phenyl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 1H NMR (400.0 MHz, CDCl3) d 2.0-2.2 (m, 2H), 3.0-3.2 (m, 2H), 3.83-3.9 (m, 4H), 7.6-7.7 (m, 3H), 8.05 (d, 2H), 8.25-8.3 (m, 4H) and 8.85 (s, 1H) ppm; MS (ES+) 435.2 Compound IA-134 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(2-phenylphenyl)pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 7.2-7.28 (2H, m), 7.3-7.35 (1H, m), 7.45-7.5 (1H, m), 7.55-7.6 (3H, m), 7.65-7.7 (3H, m), 7.75-7.8 (1H, m), 7.72 (1H,$) and 8.1-8.15 (2H, m) ppm; MS (ES+) 392.3 Compound IA-184 5-(2-ethylsulfanylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 1H NMR (400.0 MHz, CDCl3) d 1.25 (t, 3H), 3.95 (q, 2H), 7.4-7.5 (m, 2H), 7.5-7.65 (m, 5H), 8.25 (d, 2H) and 8.6 (s, 1H) ppm; MS (ES+) 376.2 Compound IA-207 5-(2-oxazol-5-ylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 1H NMR (400.0 MHz, DMSO) d 7.6-7.8 (m, 9H), 8.1-8.13 (m, 2H), 8.15 (s, 1H) and 8.18 (s, 1H) ppm; MS (ES+) 383.1 Compound IA-229 5-(2-isopropylsulfonylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 1H NMR (400.0 MHz, CDCl3) d 1.35 (d, 6H), 3.4-3.5 (m, 1H), 7.0 (br s, 2H), 7.4-7.45 (m, 2H), 7.5-7.65 (m, 5H), 8.2-8.25 (m, 2H) and 8.55 (s, 1H) ppm; MS (ES+) 390.2
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([CH:23]=[CH:24][C:25](OC)=[O:26])=[CH:21][CH:20]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:29][CH:30]=1
Reactant: COC(=O)C=Cc1ccc(OCc2nc(-c3ccc4ccccc4c3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/CO)cc1

Procedure:
According to the method described for Reference Example 23, methyl 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]cinnamate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2-propen-1-ol. Recrystallization from chloroform-ether gave colorless prisms, m.p.159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-chlorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.19 (1H, d, J=7.7 Hz), 8.65 (1H, d, J=2.4 Hz), 7.98–7.92 (3H, m), 7.51 (2H, d, J=8.4 Hz), 7.23–7.18 (3H, m), 7.09–7.06 (1H, m), 5.20–5.10 (1H, m), 4.18 (1H, d, J=14.2 Hz), 4.12 (1H, d, J=14.2 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.0 Hz); MS (ESI) m/z 443 (M+H)+, 441 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@@H:18]([F:40])[CH2:19][O:21]2)[N:6]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1

Procedure:
Following the procedure for Intermediate 65 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24) gave tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate as a solid (350 mg, 73% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.31 (s, 1H), 7.98 (s, 1H), 5.15-4.98 (m, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.77 (d, J=8.7 Hz, 1H), 4.39-3.94 (m, 2H), 3.80 (s, 3H), 2.12-1.93 (m, 4H), 1.85 (d, J=11.0 Hz, 1H), 1.52 (s, 9H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[OH:8]
Reactant: COc1c(C)cc(CCCCO)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CCCCO)cc(C)c1O

Procedure:
A solution of 4-[3,5-dimethyl-4-methoxyphenyl]butanol (PREPARATION NA-14, 4.96 g), boron tribromide (1.0M in methylene chloride, 47 ml) in methylene chloride (200 ml) is stirred at -70° and then allowed to warm to 20°-25° over 4 hr. The reaction did not begin until the reaction reached room temperature. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated to give the phenol which had a consistent NMR. A sample of the phenol (5.00 g) is dissolved in methylene chloride (100 ml) and is treated at 0° with triethylamine (6.28 g) and methanesulfonyl chloride (7.09 g). After 3 hr, the reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated to give the title compound which had an NMR consistent for the bis-mesylate.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[Li].[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38])=[O:23])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid, lithium salt (for a preparation see Intermediate 9)(169 mg, 0.384 mmol) and 2-aminopropane-1,3-diol (69.9 mg, 0.767 mmol) in DMF (2 ml) were added HATU (190 mg, 0.499 mmol) and DIPEA (0.201 mL, 1.151 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide (83 mg, 42%) as a colourless oil. LCMS (Formate, 2 min), Rt=0.73 min, MH+=514.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(O)(=O)C(C)(C)C.[F-].[Cs+].Br[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=1.[CH:45]1([C@H:49]([NH:51][C:52]2[C:57]3[N:58]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=4)[CH:59]=[N:60][C:56]=3[C:55]([CH3:72])=[C:54]([C:73]#[N:74])[N:53]=2)[CH3:50])[CH2:48][CH2:47][CH2:46]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:45]1([C@H:49]([NH:51][C:52]2[C:57]3[N:58]([CH2:61][C:62]4[CH:63]=[CH:64][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:67]=4)[C:59]([C:36]4[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=4)=[N:60][C:56]=3[C:55]([CH3:72])=[C:54]([C:73]#[N:74])[N:53]=2)[CH3:50])[CH2:48][CH2:47][CH2:46]1
Reactant: Cc1c(C#N)nc(N[C@H](C)C2CCC2)c2c1ncn2Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)c1ccnc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: Cc1c(C#N)nc(N[C@H](C)C2CCC2)c2c1nc(-c1cc(C(C)C)ccn1)n2Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a vial containing palladium(II) acetate (4.3 mg, 0.019 mmol) and butyldi-1-adamantylphosphine (13.9 mg, 0.039 mmol) was added 1,4-dioxane (300 ul). The vial was evacuated and refilled with Ar (3×). The solution was warmed to 70° C. for 20 minutes. In a separate vial were combined pivalic acid (9.9 mg, 0.097 mmol), cesium fluoride (44 mg, 0.29 mmol), 2-bromo-4-isopropylpyridine (purchased from CombiPhos Catalysts, Inc.) (29 mg, 0.15 mmol), (R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (40 mg, 0.097 mmol) and 1,4-dioxane (0.5 mL). The mixture was degassed with Ar for 15 minutes, and the catalyst solution was added to the mixture. The resulting mixture was stirred at 130° C. for 3 days. The mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to give (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C30H31F3N6 [M+H]+ 533. found 533.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([OH:13])=[CH:5][CH:4]=1)=[O:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:16][CH:15]=[CH2:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C=O)cc1C(=O)OC
Yield: 106 %

Procedure:
Methyl 5-formylsalicylate (3.3 g, 18 mmol), allyl bromide (1.7 mL, 20 mmol), and potassium carbonate (2.8 g, 20 mmol) were stirred at room temperature in DMF (20 mL) overnight. After concentration, the mixture was diluted with EtOAc and extracted with water (5×), then brine. After drying (MgSO4), solvent was removed to give a yellow solid (4.2 g). 1H-NMR(300 MHz, CDCl3): 9.92 (s, 1H), 8.35 (d, 1H, J=2 Hz), 8.00 (dd, 1H, J=9,2 Hz), 7.09 (d, 1H, J=9 Hz), 6.13-6.01 (m, 1H), 5.58-5.34 (m, 2H), 4.75-4.73 (m, 2H), 3.93 (s, 3H). Anal. Calc'd for C12H12O4 : C, 65.45; H, 5.49; Found: C, 65.10; H, 5.36.