Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)[CH3:34]>ClCCl>[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][CH:38]=1)[CH3:34]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.15 g, 0.40 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.139 ul, 1.0 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid ethyl ester (92.0 mg, 0.48 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1Hindol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid ethyl ester as a white solid. (Yield 0.14 g, 60.8%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine)palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline, 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[CH2:16]([O:18][CH:19]([O:28][CH2:29][CH3:30])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH3:17]>>[CH2:29]([O:28][CH:19]([O:18][CH2:16][CH3:17])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:8]([CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)=[CH:22][CH:21]=1)[CH3:30]
Reactant: Cn1ccnc1CNCc1nccn1C
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Product: CCOC(OCC)c1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1

Procedure:
The same procedure as in Example 3 was carried out, except that 1-(1-methyl-1H-imidazol-2-yl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methaneamine (International Publication WO 2007/058322 pamphlet, Example 58) was used in place of the compound obtained in Example 2, and 4-(diethoxymethyl)benzaldehyde (CAS Registry Number: 81172-89-6) was used in place of isobutylaldehyde in Example 3, the title compound having the following physical properties was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([OH:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH:21]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Yield: 96.7 %

Procedure:
Using the method of Example 21.2, 4-fluoro-3-nitrobenzotrifluoride (7.4 g) and 3-chloro-5-hydroxypyridine (4.59 g) were heated with potassium carbonate (5.4 g) in DMF at 80° C. for 1 h, then 60° overnight. Workup gave the title compound (10.9 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].Cl.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[NH:35][N:34]=[N:33][N:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(C#N)nn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(-c2nnn[nH]2)nn1
Temperature: 102.5 °C
Yield: 74 %

Procedure:
6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]-3-cyanopyridazine (reference example 14) (1.63 g) was dissolved in dimethylacetamide (DMA) (17 mls) under argon. Triethylamine hydrochloride (0.87 g, 6.3 mmol) and sodium azide (0.82 g, 12.6 mmol) were added and the mixture heated at 95-110° C. for 3 hours. It was then cooled and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2N HCl saturated aqueous ammonium chloride (×2) and brine (×2), dried over Na2SO4, filtered and evaporated. The residue was recrystallised from acetonitrile to give the title product (1.34 g, 74.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:20](C1C=CC2N(C=C(C(OCC)=O)N=2)C=1)#[N:21]>>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]#[N:21])=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn2cc(C#N)ccc2n1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Product: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1

Procedure:
By working in the same manner as for the preparation of Intermediate 1, replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate with ethyl 6-cyanoimidazo[1,2-a]pyridine-2-carboxylate (J. Med. Chem. (1998), 41(22), 4317), N-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide is obtained in the form of a yellow solid
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrBr.[C:12](=O)(O)[O-].[Na+]>C(O)(=O)C.CCCCCC>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 28 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexane and passed through a pad (600 mL funnel) of silica gel eluting with hexane to afford a white solid which was diluted with cold (dry ice-acetone) hexane and collected by filtration to afford 4.7 g (28%) of the title compound as a white solid, m.p. 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH3:16][C:17]1([CH3:45])[CH2:43][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[C:39]([OH:41])=O)[CH:34]=[CH:35][CH:36]=3)=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:24][C:20]=2[C:19](=[O:44])[CH2:18]1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C(Cl)Cl>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:39](=[O:41])[C:38]([NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:22]2[C:21]3[CH2:43][C:17]([CH3:16])([CH3:45])[CH2:18][C:19](=[O:44])[C:20]=3[S:24][C:23]=2[N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:32]=1)=[O:42]
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Reactant: CN(C)CCN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNC(=O)C(=O)Nc1cccc(-c2c(N3CCOCC3)sc3c2CC(C)(C)CC3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
Isobutyl chloroformate (30 μL, 0.23 mmol) and triethylamine (30 μL, 0.23 mmol) were added to a solution of Example 292 (50 mg, 0.12 mmol) in DCM (5.0 mL) and the reaction mixture was stirred at room temperature for 1 h. N,N-Dimethylethylenediamine (60 μL, 0.58 mmol) was then added and the reaction mixture was stirred at room temperature for 72 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 5.8) to give the title compound (4 mg, 6%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.41 (1H, br s), 7.55-7.46 (2H, m), 7.29 (1H, t, J 7.9 Hz), 7.05-7.00 (1H, m), 3.61-3.49 (6H, m), 2.90-2.77 (6H, m), 2.49 (6H, s), 2.33 (2H, s), 2.29 (2H, s), 0.90 (6H, s). LCMS (ES+) 499.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2Cl)(=O)C>CC(O)C>[CH2:1]([NH:8][C:16]1[C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([OH:12])[CH:14]=2)[N:19]=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2ncnc(NCc3ccccc3)c2cc1O
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Benzylamine (1.28 g, 12.0 mmol) was added into a mixture of compound 0105 (1.0 g, 4.0 mmol) and 2-propanol (50 ml). The reaction mixture was then stirred at reflux for 3 hours. The mixture was cooled to room temperature and the resulting precipitate was isolated. The solid was then dried to give the title compound 0701-85 as a yellow solid (854 mg, 76%): LCMS: 282 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:24](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:24][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[N:11]=2)[C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2nc(C)ccc2c1=O
Reaction time: 17 h
Yield: 63.1 %

Procedure:
A mixture of 9.7 g (0.0417 m) of ethyl 1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, 11.5 g (0.0834 m) of potassium carbonate and 200 ml of dimethylformamide was slurried at room temperature, and 8.3 g (0.0417 m) of O-(2,4-dinitrophenyl)hydroxylamine was added. The reaction mixture was stirred for 17 hours and then concentrated in vacuo. The residue was dissolved in 1 liter of warm water and extracted with 800 ml of chloroform. The extracts were filtered, dried over anhydrous magnesium sulfate, decolorized with charcoal and concentrated in vacuo. The residue was recrystallized from ethanol and chromatographed on silica gel, using isopropyl alcohol-chloroform (1:9) for elution, to give 6.5 g of ethyl 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, buff-colored solid, m.p. 173°-174° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]([NH:10][CH:11]([C:13]1[N:18]=[N:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[N:15][CH:14]=1)[CH3:12])=O)=[O:4].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:17]2)=[C:11]([CH3:12])[N:10]=1)=[O:4]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(C)(C)C)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4NC(=O)C(C)(C)C)n3n2)cc(OC)c1OC
Yield: 9.9 %

Procedure:
In a similar manner as described for Example 1, 2-[(2,2-dimethylpropanoyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 15) (0.040 g, 0.080 mmol) in 1,2-dichloroethane (10 mL) and phosphorus oxychloride (0.060 mL, 0.64 mmol) gave 2,2-dimethyl-N-(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)propanamide (0.0039 g) as a yellow solid. 1H NMR (CDCl3): δ8.87 (s, 1H), 8.66 (dd, J=8.6, 1.2 Hz, 1H), 8.62 (dd, J=8.1, 1.6 Hz, 1H), 7.43-7.37 (m, 1H), 7.16-7.11 (m, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 6.87 (s, 2H), 3.84 (s, 3H), 3.77 (s, 6H), 2.62 (s, 3H), 1.34 (s, 9H). MS m/z 491 (M+1).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]=1>>[C:1]1([C:7]#[C:8][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: IC1=CCCc2ccccc21
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccccc1)C1=CCCc2ccccc21

Procedure:
The modified procedure was used to convert phenylacetylene and 1,2-dihydro-4-iodonaphthalene to the title product in 24 hours. Purification by flash chromatography (20% CH2Cl2 in hexanes) gave the analytically pure product as a light yellow oil (360 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.58, 1H), 7.52 (m, 2H), 7.31 (m, 3H), 7.25 (m, 1H), 7.18 (t, 1H), 7.13 (d, J=7.33, 1H), 6.54 (t, 1H), 2.80 (t, 2H), 2.42, (m, 2H). 13C NMR (100 MHz, CDCl3) δ 135.49, 135.05, 132.64, 131.54, 128.29, 128.07, 127.66, 127.39, 126.62, 125.05, 123.43, 121.72, 90.28, 87.29, 27.14, 23.69. Anal. Calc'd. for C18H14: C, 93.87; H, 6.13; Found C, 93.79; H, 6.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9](=O)N(C)C.C[O-].[Na+].C(=O)([O-])N.C[O-].[Na+].CO.[Br:31][CH2:32][CH2:33]CBr>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:33][CH2:32][Br:31]
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: BrCCCBr
Agent: C[O-]
Agent: NC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-chloro-4-dimethylcarbamoylthiophenylacetate (8.5 g, 0.0295 mol) in methanol (30 mL) was added 25% NaOMe in methanol (7.0 mL, 0.034 mol). The reaction was heated to reflux for 2 h. TLC analysis shows residual starting carbamate. Additional NaOMe/MeOH (1.0 mL) was added and the mixture stirred an additional 30 min at reflux. After cooling to ambient temperature, the thiolate solution was added dropwise to a solution of 1,3-dibromopropane (12 mL, 0.12 mol) in methanol (30 mL). The resulting solution was refluxed for 3 h then cooled to ambient temperature, After standing overnight, the reaction was quenched by pouring into ice water. After adjusting to pH1 with conc. HCl, the aqueous solution was extracted with EtOAc (0.2 L then 2×0.1 L). The combined organics were washed with water, brine, dried over anhyd. MgSO4, filtered, and concentrated. The residue was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([O:17]CC)=[CH2:16])[N:12]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:10]=2)[CH2:3]1.O.Cl>O1CCOCC1>[F:35][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[N:10]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=2)[CH2:3]1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a solution of 4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (17 mg, 0.04 mmol) in dioxane (3 mL) was added water (0.2 mL) and HCl (9 μL, 0.11 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvents were evaporate and the residue was partitioned between aqueous sodium bicarbonate and DCM. The organic phase was evaporated to give the title compound (16 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH3:28]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole from step 3 (1.81 g, 4.3 mmol) and ethyl iodide (0.86 g, 5.5 mmol) were stirred vigorously in 20 mL dry dimethylformamide (DMF) with finely powdered potassium carbonate (0.58 g, 4.2 mmol) under nitrogen at 25° C. for 18 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole was isolated by chromatography on silica gel using ethyl acetate/toluene (10/90) as the eluant, giving 0.65 g (69%) of a white solid: mp 133-135.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[CH:18]=[N:17][C:16](Br)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[N:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 90 °C
Yield: 63 %

Procedure:
Nitrogen was bubbled through a solution of 3-methoxyphenyl boronic acid (393 mg, 2.59 mmol), 2-amino-5-bromopyrazine (300 mg, 1.72 mmol), sodium carbonate (603 mg, 5.69 mmol), dimethoxyethane (10 mL), and water (3 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 40/60 hexanes/ethyl acetate) afforded 5-(3-methoxy-phenyl)-pyrazin-2-ylamine (218 mg, 63%) as a light yellow solid: mp 113.2–115.5° C.; EI-HRMS m/e calcd for C11H11N3O (M+) 201.0902, found 201.0905.
Reaction SMILES: BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:22][C:23]1[C:24]([C:40]([OH:42])=O)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)=[CH:27][N:28]=1.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]([NH:50][NH2:51])=O.CCN(C(C)C)C(C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:36]([CH3:37])[CH3:38])=[O:39])=[CH:33][CH:34]=2)=[N:25][C:24]=1[C:40]1[O:42][C:48]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)=[N:50][N:51]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: NNC(=O)c1ccco1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccco4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Dibromo(triphenyl)phosphorane was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (100 mg, 0.35 mmol) and furan 2-carbohydrazide (44.1 mg, 0.35 mmol) in acetonitrile (3.0 mL) at room temperature. Bright yellow solution observed. The resulting solution was stirred at room temperature for 30 min. After this time, DIPEA (304 μL, 1.75 mmol) was added dropwise and the reaction mixture stirred at room temperature for 30 min. The reaction mixture was filtered to leave a yellow solid. The solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to give the product as a yellow solid (67.6 mg, 51% yield); 1H NMR (400.0 MHz, DMSO) d 2.97 (m, 6H), 6.87 (m, 1H), 7.54-7.56 (m, 3H), 7.57 (br s, 2H), 8.15 (m, 3H) and 8.98 (1H, s) ppm; MS (ES+) 377.17
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]2[O:10][CH2:11][C:12]3[N:37]=[CH:36][CH:35]=[CH:34][C:13]=3[C:14](=[CH:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][C:21]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([OH:24])[C:20]([CH3:33])([CH3:32])[CH2:19]3)[C:8]=2[CH:7]=1.[OH-].[Na+]>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2([OH:24])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]=[C:14]3[C:13]4[CH:34]=[CH:35][CH:36]=[N:37][C:12]=4[CH2:11][O:10][C:9]4[CH:38]=[CH:39][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][C:8]3=4)[CH2:19][C:20]2([CH3:32])[CH3:33])=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CN(CCC=C2c3cc(OCC(=O)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-acetic acid methyl ester (0.060 g, 0.107 mmol) was dissolved in methanol (1.5 mL). Sodium hydroxide (150 uL, 1N stock solution) was added and the resulting mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo to give a yellow oil. The oil was suspended in water (2 mL) and then washed with ethyl acetate (3×3 mL). The aqueous layer was then acidified to pH=2 and extracted with ethyl acetate (3×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a white solid (55 mg, 94%).