Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]([OH:14])[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=O)[O:3][CH:2]=1.[N:15]#[C:16][NH2:17].[O-]CC.[Na+].O>C(O)C>[NH2:17][C:16]1[O:14][C:6]([C:4]2[O:3][CH:2]=[CH:1][CH:5]=2)=[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: O=C(c1ccco1)C(O)c1ccco1
Reactant: N#CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccco2)c(-c2ccco2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a dark brown crystal.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: Oc1ccc(Oc2cnc3ccccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-hydroxyphenoxy)quinoline (2.4 g), ethyl 2-bromopropionate (2.1 g), anhydrous potassium carbonate (3.3 g) and dimethylformamide (50 ml) was stirred and heated at 80° C. for 4 hours. The mixture was poured into water (500 ml) and extracted with diethyl ether (2×100 ml). The ether extracts were dried, evaporated to dryness and then chromatographed on silica gel (100 g) with dichloromethane elution. Ethyl 2-[4-(3-quinolinyloxy)phenoxy]-propionate was obtained as a pale yellow oil (1.9 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.75 (1H, d); 8.1 (1H, bd); 7.7-7.3 (4H, m); 7.0 (4H, s, phenoxy protons); 4.75 (1H, q, CH--CH3); 4.25 (2H, q, OCH2 --CH3); 1.65 (3H, d, CH--CH3); 1.25 (3H, t, OCH2 --CH3).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].[CH2:23]([N:25]1[C:29]2=[N:30]C=C(C(OCC)=O)C(NN)=C2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:30][C:29]4[N:1]([N:2]=[CH:23][N:25]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Product: O=c1[nH]c2ncnn2c2c1cnc1c2cnn1Cc1ccco1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1, 8-furfuryl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 4, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 8-furfuryl-4-phenyl-4H-pyrazolo[4',3': 5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(N2CCCCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCCCCC3)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 4-chloro-6-(hexahydro-1H-azepin-1-yl)-2-pyrimidinamine (600 mg, 2.65 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.437 g, 2.65 mmol) in 1,4-dioxane (10.6 mL). Saturated aqueous NaHCO3 (2.65 mL) was added, and the resulting mixture was degassed with nitrogen for 5 minutes. Pd(Ph3P)4 (0.153 g, 0.13 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature, and the organic layer was separated and concentrated. The resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (eluent: 90/10/1 CHCl3/CH3OH/NH4OH) afforded the title compound (547 mg, 62%) as a yellow solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][S:55][CH3:56])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:56][S:55][CH2:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CSCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (360 mg) was added toluene/ethanol/water (10/1/1, 14.2 ml) and then were added 4-(2-methylthioethoxy)phenyl borate (241 mg) and potassium carbonate (216 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (41 mg), and the mixture was stirred at 100° C. for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-methylthioethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 85) (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (Intermediate 47) (2 g, 6.56 mmol) was dissolved in acetic anhydride (Aldrich, 6.75 mL, 92 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and the resulting precipitate was isolated by filtration and dried. The solid was triturated with methanol, filtered and dried to give the title compound methyl 4-acetamido-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (2.05 g, 5.91 mmol, 90% yield) as beige solid. LCMS: (M+H)+=347; Rt=3.76 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.Br[CH:14]([CH2:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:14]([CH2:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:16])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: CCC(Br)C(=O)NC(C)(C)C#CCCCCl
Product: CCC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)C#CCCCCl

Procedure:
In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinoline was reacted with 2-bromo-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide to give 2-(3-bromo-6-quinolinyloxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide as a colourless oil. 1H NMR (CDCl3) δ: 1.04–1.10(3H, t); 1.60(6H, s); 1.86–1.94(2H, m); 2.00–2.06(2H, m); 2.32–2.36(2H, t); 3.60–3.64(2H, t); 4.56(1H, t); 6.34(1H, s); 7.02 (1H, m); 7.42–7.46(1H, dd); 8.03 (1H, d); 8.22(1H, s); 8.78(1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27](Cl)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C>[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=4)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[N:26][N:25]=1
Reactant: Fc1ccc(F)c2c(Cl)nnc(Cl)c12
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c(F)ccc(F)c34)cc2)n1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.100 g, 0.34 mmol) and 1,4-dichloro-5,8-difluorophthalazine (0.096 g, 0.41 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated to 100° C. in a sealed tube for 45 min. The reaction was diluted with diethyl ether and the resulting solids were filtered and triturated with EtOAc. The solids were dried to yield 4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a dark gray solid. MS m/z=492 [M+H]+. Calc'd for C24H16ClF2N7O: 491.89.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]Br)[CH2:25][CH2:24]1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC[C@H]1CC[C@H](CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)cc2)nc1

Procedure:
A mixture of 11 g of 2-p-hydroxyphenyl-5-n-hexylpyrimidine, 7.8 g of trans-4-n-propyl-1-bromomethylcyclohexane, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is warmed at 90° for 10 hours. Customary working up gives 4-(5-n-hexylpyrimidin-2-yl)-phenyl trans-4-n-propylcyclohexylmethyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh3)2Cl2 (630 mg, 0.898 mmol, 0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. After further stirring at 80° C. for 2 hr under nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml), and further stirred for 30 min. The precipitates were filtered and washed with water (50 ml). They were further washed with CH3CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(O)(=O)C=C.C(O)(=O)C=C.[CH3:16][C:17](C)(C)[CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[C:1]([O:5][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CCC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CC(=O)OCCCC

Procedure:
7% by weight of trimethyl propane triacrylate 14.1 g of azobisisobutyronitrile.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: CN=C=O
Reactant: NC1CCC(=O)c2ccccc21
Product: CNC(=O)NC1CCC(=O)c2ccccc21

Procedure:
In the manner described in Example 19, 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine is allowed to react with methyl isocyanate to afford the title compound, m.p. 220° C. to 223° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][S:9]C(=O)C.[S-2].[Na+].[Na+].Cl>CO.O>[CH2:13]([CH:7]([CH2:8][SH:9])[C:6]([N:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:4][C:3]([OH:28])=[O:2])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CN(C(=O)C(CSC(C)=O)Cc1ccccc1)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: O=C(O)CN(C(=O)C(CS)Cc1ccccc1)c1ccccc1F
Reaction time: 1 h

Procedure:
A solution of the N-(S-acetyl-2'-benzyl-3'-mercaptopropionyl)-2-fluorophenylglycine methyl ester of Example 19b (0.2 mmol) in methanol (2 ml) was degassed with argon for 20 minutes then treated with a solution of sodium sulphide (1 mmol) in degassed water (2 ml). After 30-90 minutes, 0.25M aq. HCl (20 ml) was introduced and the mixture extracted with ethyl acetate (3×20 ml). The dried (MgSO4) organic phases were evaporated to give the title compound as a clear oil, an approximately equimolar mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([NH:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[O:10])[CH:5]=[CH:4][N:3]=1.C(OC([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:8][C:7]1[C:2]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:3][CH:4]=[CH:5][C:6]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2)=[O:10]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(N2CCNCC2)c1Cl
Yield: 26.6 %

Procedure:
A solution of 2,3-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.15 g, Example 10a) and 1-t-butoxycarbonylpiperazine (0.19 g) in dimethylsulfoxide (2 ml) was heated at 100° C. for 8 hours. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol and treated with 4M HCl in dioxan (4 ml). Once deprotection was complete the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.050 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCNCc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
[[2′-[(t-Butylamino)sulfonyl]-1,1′-biphenyl-4-yl]methyl] bromide (0.94 g), n-heptylamine (0.28 g) and potassium carbonate (0.35 g) were added to dimethylformamide and the mixture was stirred at room temperature. Sixteen hours and 30 minutes later, ethyl acetate (30 mL) was added, and the resulting mixture was washed three times with brine (100 mL, each). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (chloroform/ethyl acetate) to afford N-[[2′-[(t-butylamino)sulfonyl]-1,1′-biphenyl-4-yl]methyl]-N-heptylamine as a yellow oil (0.43 g). Yield: 42%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:16])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1ccc(CO)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of 4.20 g (23.1 mmol) (4-allyloxy-2-fluoro-phenyl)-methanol in 80 ml dichloro-methane and 0.5 ml DMF was cooled to 0° C. 2.17 ml (3.57 g, 30.0 mmol) thionyl chloride were added slowly and then stirred for 1 h at room temperature. Dichloromethane was distilled off. The residue was taken up in 100 ml ethyl acetate and washed with concentrated sodium carbonate solution. The organic phase was dried and evaporated to give 4.47 g (97%) 1-allyloxy-3-fluoro-4-chloromethyl-benzene as colored oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: BrBr
Reactant: Nc1cccc(F)c1F
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(F)c1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
2,3-difluoro-phenylamine (13.45 g, 104.2 mmol) was diluted with acetic acid (180 ml), bromine (2.6 ml) diluted with acetic acid (5 ml) was slowly added thereto at 0° C., and the solution was stirred for 5 hours. The resulting solution was distilled under a reduced pressure to remove the solvent, basified by adding 50% sodium hydroxide solution (250 ml), and extracted with dichloromethane (200 ml) twice. The separated organic layer was dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain the title compound 6.46 g (yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.CO.[CH:29]1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([O:17][CH3:29])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-indazol-1-ylacetic acid prepared as described in Example 3 (0.319 g) was suspended in dry dichloromethane (6 cm3) and methanol (0.04 cm3) and DMAP (10 mg) added. Dicyclohexylcarbodiimide (0.169 g) was added and the mixture stirred at room temperature for 2 hours and left to stand overnight. The mixture was filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (hexane: TMBE,3:2) to yield methyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-1-yl]acetate (0.28 g) as an oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:28](B(CC)CC)[CH3:29].O>CN(C=O)C.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][CH3:29])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Reactant: CCB(CC)CC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(CC)cc(Cl)c2OC1C(F)(F)F
Temperature: 110 °C

Procedure:
To a solution of 500 mg (1.16 mmol) ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 3 mL of anhydrous DMF was added 0.481 g (3.48 mmol, 3.0 eq.) of potassium carbonate, 0.134 g (0.116 mmol, 0.1 eq.) of tetrakis(triphenylphosphine)-palladium(0) and 1.74 mL (1.74 mmol, 1.5 eq.) of 1M triethylborane in THF. The vessel was heated to 110° C. for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was treated with water and extracted with ethyl acetate. The organic layer was washed 4 times with water and 2 times with brine, dried over sodium sulfate, filtered and concd in vacuo. The product was carried to the next step without further purification.