Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31]C)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:41](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:41])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
A mixture of 0.075 g (0.129 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194), 4 mL of dimethylformamide, 0.0654 g (0.167 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.12 mL (0.689 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0159 g (0.297 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0346 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzamide (I-203).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:17]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: COC(C)(C)CN
Product: COC(C)(C)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 71 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 2-methoxy-2-methylpropan-1-amine, providing the title compound as yellow solid (71%).
Reaction SMILES: O.O.O.[O-:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+].Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.O>C(#N)C>[Br:19][C:17]1[N:18]=[C:13]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([NH2:20])=[N:15][CH:16]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1ncc(Br)nc1Oc1ccccc1

Procedure:
Sodium phenoxide trihydrate (0.5 g) and 3,5-dibromo-2-pyrazinamine (0.5 g) in acetonitrile (20 mL) were heated at reflux for 7 hours. After cooling, water was added and the reaction mixture extracted with ethyl acetate (x2). The combined extracts were dried (MgSO4) and the solvent evaporated to give the sub-title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C=O)C>O>[CH2:9]([N:5]1[C:4](=[O:12])[C:3]2[NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:1][C:2]=2[NH:7][C:6]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A mixture of 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (30 g, 0.068 mol), P2O5 (34.0 g, 0.240.8 mol) and DMF (300 ml) were heated at 100° C. for 30 minutes. The reaction mixture was cooled to 20-25° C. The reaction mixture was slowly poured into water (1.5 L) with vigorous stirring. Solid material separated was filtered off, and washed with water (200 ml) to obtain 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (25 g, 88%) as a pale yellow solid.
Reaction SMILES: O=[C:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:10]([O:12]CC)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][N:25]2[C:10](=[O:12])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:2]=3[N:15]=[C:16]2[CH:17]=1)=[O:20]
Reactant: CCOC(=O)C1CCCCCCC1=O
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Temperature: 25 °C
Yield: 10.9 %

Procedure:
A solution of ethyl 2-oxocyclooctanecarboxylate (1 g, 5.05 mmol) and methyl 2-aminoisonicotinate (0.768 g, 5.05 mmol) in PPA (2.5 mL) and 1,2-dichloroethane (5 mL) was stirred at 85° C. for 18 hours. The reaction mixture was then cooled to ambient temperature. A chilled saturated sodium carbonate solution was added to adjust pH to 8. The resulting mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography purification to afford 157 mg of desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.FC(F)(F)C(OCC)=O>CN(C)C=O>[NH:1]=[C:2]1[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: CCOC(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: N=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 60 °C
Yield: 12.1 %

Procedure:
To a suspension of 0.5 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 15 ml of dimethylformamide is added 0.6 ml of ethyl trifluoroacetate at a temperature in the region of 20° C. The reaction medium is heated at 60° C. for 5 hours and is then cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa). The residue is taken up in dichloromethane and the insoluble product is filtered off, washed and dried. After purification by flash chromatography using a mixture of ethyl acetate and methanol (90/10 by volume) as eluent, 0.06 g of 10-imino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a reddish powder, the melting point of which is greater than 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: from 7.20 to 7.50 (mt, 2H: --H 7 and --H 8); 7.57 and 8.33 (2s, 1H each: --H of the imidazole); 7.65 and 7.86 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); from 11.10 to 12.10 (broad mult., 1H: --CONH--)).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N+:17]([O-])=O)=[CH:7][CH:6]=1>P(OCC)(OCC)(OCC)=O>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[NH:17][C:7]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccncc1-c1ccc(CCCF)cc1
Solvent: CCOP(=O)(OCC)OCC
Product: FCCCc1ccc2c(c1)[nH]c1ccncc12
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A solution of 3-(4-(3-fluoropropyl)phenyl)-4-nitropyridine (12 mg, 0.046 mmol) in 0.3 mL of triethyl phosphate was heated at 125° C. for 1 h. After cooling to rt, the volatiles were removed under reduced pressure and the residue was purified by silica chromatography (MeOH in DCM, 0% to 10%) to afford a off-white solid. This material was then further purified by reversed phase HPLC to yield 7-(3-fluoropropyl)-5H-pyrido[4,3-b]indole as a white solid (3 mg, 28%). 1H NMR (400 MHz, methanol-d4): δ 9.15 (s, 1H), 8.32 (d, J=4.4, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.44 (d, J=6 Hz, 1H), 7.37 (m, 1H), 7.16 (dd, J=8.0, 1.2 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 4.43 (t, J=6 Hz, 1H), 2.90 (t, J=7.6 Hz, 2H), 2.12-1.99 (m, 2H); MS (ESI) m/z [M+H]+229.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:19]3[C:24]([N:25]=2)=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:18]2[C:17]([NH:16][CH:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]4[S:3][CH:4]=[CH:5][N:6]=4)[CH2:11][CH2:12]3)=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:32][CH:31]=1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3cncnc32)cc1
Temperature: 130 °C
Yield: 26.5 %

Procedure:
A mixture of 3.3 parts of 2-bromothiazole, 5.55 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine, 2.12 parts of sodium carbonate and 18 parts of N,N-dimethylacetamide was stirred and heated for 20 hours at 130° C. After cooling, the reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in high vacuo at 100° C., yielding 1.8 parts (26.5%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl)-4-piperidinyl]-9H-purin-8-amine; mp. 165.4° C. (compound 172).
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[C:16]([O:20][C:21](=[O:37])[NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#N)=[CH:28][C:27]=1[F:34])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:37])[NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:4])=[CH:28][C:27]=1[F:34])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Reactant: CC(C)(COc1ccc(C#N)cc1F)NC(=O)OC(C)(C)C
Product: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C

Procedure:
Synthesized from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl[2-(4-cyano-2-fluorophenoxy)-1,1-dimethylethyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (715 mg).
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]([CH:12]([NH:15][C:16]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH2:13][CH3:14])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]2=[C:12]([CH2:13][CH3:14])[N:15]=[C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(C(C)(C)C)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(C(C)(C)C)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 150 mg (0.50 mmol) crude N-[1-(3-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclopentanecarboxamide, 80 mg (0.50 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1.[I-].[K+].O>CS(C)=O.C(OCC)(=O)C>[C:13]1([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][C:1]#[N:2])[CH2:8][CH2:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: ClCCC1CCN(c2nccc3ccccc23)CC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#CCCC1CCN(c2nccc3ccccc23)CC1
Temperature: 120 °C

Procedure:
0.63 g (9.57 mmol) of potassium cyanide is added portionwise to a suspension of 2.63 g (9.57 mmol) of 1-[4-(2-chloroethyl)-1-piperidyl]isoquinoline, prepared in step 2.2, and 0.048 g (0.29 mmol) of potassium iodide in 30 ml of dimethyl sulfoxide. The reaction mixture is maintained at about 120° C. for 16 hours. The mixture is allowed to cool to room temperature and 90 ml of water and ethyl acetate are then added. The aqueous phase is separated out and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: C(O)C.[O-]CC.[Na+].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24]CS([O-])(=O)=O)[CH2:20][CH3:21]>O>[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][CH3:21]
Reactant: CCCOC(C)CCS(=O)(=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCOC(C)CC(C(=O)OCC)C(=O)OCC
Yield: 65.8 %

Procedure:
Into 345 ml of ethanol, 43.4 g of 95%-sodium ethoxide was added, and under stirring, 114 g of diethyl malonate was added dropwise at 33°-36° C. in 55 min. After further 30 min. of stirring, 114 g of the above 2-propoxypropylmethane sulfonate was added at 34°-38° C. in 1 hour. The mixture was heated and refluxed at 80°-82° C. for 18 hours. After the completion, the product was poured in cold water and extracted with benzene, followed by washing with water, removed by distillation of benzene, and vacuum distillation to obtain 100 g of ethyl 4-propoxy-2-ethoxycarbonylvalerate (75°-115° C./5 mmHg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Yield: 99.9 %

Procedure:
Stir the mixture of 1-(chloromethyl)-3-nitro-5-(trifluoromethyl)benzene (640 mg, 2.68 mmol) and N-methylpiperazine (536 mg, 5.36 mmol) in THF (8 mL) for 2 hrs at 60° C. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain the crude product (812 mg, 100%). MS: (M+1): 303.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)[S:5][CH:6]=1.[OH-].[K+].O.NN.Cl>C(O)CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH:9]2[CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: O=C(c1cc(Br)cs1)C1CC1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: Brc1csc(CC2CC2)c1
Temperature: 160 °C

Procedure:
(4-bromo-2-thienyl)(cyclopropyl)methanone (1.02 g, 4.4 mmol) was diluted in ethylene glycol (3.75 mL). Potassium hydroxide (809 mg, 14.4 mmol, 3.3 eq) and hydrazine hydrate (0.58 mL, 18 mmol, 4.2 eq) were added, and the reaction mixture was heated at 160° C. for 45 minutes behind a blast shield. The reaction was cooled to room temperature, water was added, and the pH adjusted to acidic (by pH paper) with 6M aqueous HCl. The mixture was extracted with dichloromethane, the combined organics dried over sodium sulfate, filtered, and concentrated. The crude product was purified by isco combiflash, eluting with 0-10% ethyl acetate in hexanes. The title compound was obtained as clear colorless oil (50 mg, 5%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]\[Sn](CCCC)(CCCC)CCCC)[CH3:11].CN(C)C=O.[F-].[K+]>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.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCO/C=C/c1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 3.11 g of 5-bromo-2,4-dichloropyrimidine, 5.18 g of cis-1-ethoxy-2-tri-n-butylstannylethylene (synthesized according to the method disclosed in J. Am. Chem. Soc., 1977, 99, 7365), 0.479 g of dichlorobis(triphenylphosphine)palladium (II), and 60 mL of N, N-dimethylformamide was stirred for 6 hours at 70° C. After standing to cool, 60 mL of water, 60 mL of ethyl acetate, and 20 g of potassium fluoride were added thereto, and the mixture was stirred overnight at room temperature. The insolubles were filtered through celite and the filtrate was extracted with chloroform. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: 10% chloroform-hexane/ethylacetate=100/0-0/100), to obtain 1.15 g of 5-bromo-2-chloro-4-[(E)-2-ethoxyvinyl]pyrimidine [11-1] (hereinafter, referred to as the compound [11-1]) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)#[N:2].[ClH:17].[CH2:18]([OH:20])[CH3:19]>ClCCl>[ClH:17].[CH2:18]([O:20][C:1](=[NH:2])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH3:19]
Reactant: Cc1ccc(OCC#N)cc1NS(C)(=O)=O
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)COc1ccc(C)c(NS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(5-Cyanomethoxy-2-methylphenyl)-methanesulfonamide (3.48 g) was dissolved in a mixture of 70 ml of dichloromethane and 3.5 ml of ethanol. The reaction mixture was cooled in an ice bath, saturated with hydrogen chloride gas (Matheson, Newark, Calif.), and slowly allowed to come to room temperature and kept there for 16 hours. The solvent was evaporated leaving 5.2 g of 2-(4-methyl-3-methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride. ##STR77##
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:12]>O.[Cu]Cl>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:12])[CH:3]=[N:4][CH:5]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: N
Agent: Cl[Cu]
Solvent: O
Product: Nc1cncc(C(F)(F)F)c1
Temperature: 170 °C
Reaction time: 48 h

Procedure:
Prepared according to the method of Barlin et al., Aust. J Chem., 1990, 43, 1175: 3-Chloro-5-(trifluoromethyl)pyridine (3.0 g, 16.52 mmol) is suspended in water (67.5 ml) and treated with copper(I)chloride (8.18 g, 82.62 mmol). Aqueous ammonia solution (25%, 67.5 ml) is added, and the reaction is stirred for 48 hours at 170° C. in the autoclave. The reaction mixture is cooled to room temperature and extracted three times with dichloromethane. The combined organic phases are washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo to yield analytically pure product.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[CH:27][C:28]=1[F:29].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:30][C:25]5[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1ccc(F)c(F)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (40 mg) as a white solid.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.[ClH:14]>C(O)(C)C>[Cl:14][CH2:3][CH2:2]/[CH:1]=[C:4](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)\[CH3:5]
Reactant: Cl
Reactant: CC(O)(c1ccc(F)cc1)C1CC1
Solvent: CC(C)O
Product: C/C(=C\CCCl)c1ccc(F)cc1
Yield: 84 %

Procedure:
1-Cyclopropyl-1-(4-fluorophenyl)ethanol (307 mg, 1.70 mmol) in a solution of 1 N HCl in isopropyl alcohol (3.6 mL) was heated at 60° C. for 1 h. The reaction mixture was then concentrated in vacuo, and column chromatography purification yielded 1-[(1E)-4-chloro-1-methyl-1-butenyl]-4-fluorobenzene (282 mg, 84%) as a colorless oil. The title compound was isolated as a yellow oil (36 mg, 70%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-[(1E)-4-chloro-1-methyl-1-butenyl]-4-fluorobenzene (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.62 (br-s, 1H), 1.90-2.20 (m, 9H), 2.31-2.44 (m, 5H), 2.71-2.80 (m, 1H), 2.81-2.89 (m, 1H), 2.92-3.00 (m, 1H), 3.04-3.13 (m, 1H), 3.17-3.24 (m, 2H), 3.27-3.31 (m, 1H), 3.51-3.63 (m, 1H), 3.80-3.91 (m, 1H), 5.64-5.73 (m, 1H), 6.62 (t, 1H, J=7.5 Hz), 6.87 (d, 1H, J=6.6 Hz), 6.91-7.00 (m, 3H), 7.29-7.34 (m, 2H) ppm)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+].Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:17]([OH:19])=[O:18]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:16]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)COc1ccccc1O
Reactant: O=C(O)C(Br)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccccc1OC(C(=O)O)c1ccccn1

Procedure:
A mixture of 2-hydroxyphenoxy acetic acid (16.8 g. 0.1 mole) and 80 ml. of 5N aqueous sodium hydroxide (0.4 mole) is stirred until solution is effected, then the solution treated with 2-bromo-2-(2-pyridyl)-acetic acid (21.6 g. 0.1 mole), and refluxed for 20 hours. The cooled solution is taken to neutrality and the diacid crystallized from benzene to give 2-(2-pyridyl)-2-(carboxymethoxyphenoxy)-acetic acid.