Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH2:25]C)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reaction time: 40 h

Procedure:
A solution of 130.15 g of sodium methoxide in 2.4 L methanol is added at room temperature to a solution of 5469 g of ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate in 52.3 L of methanol. The mixture is stirred for 40 hours under nitrogen. Glacial acetic acid (145.5 g) is added and the reaction mixture is evaporated to dryness at 60° and 3 mm Hg. The residue is dissolved in 40 L of ethyl acetate, the solution is washed with dilute sodium bicarbonate solution and then with 5% sodium bisulfite, dried over sodium sulfate, treated with charcoal and evaporated to dryness to yield crude methyl 8-(p-chloro-phenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate.
Reaction SMILES: [OH:1][CH:2](/[CH:12]=[CH:13]/[C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+].O>CO>[OH:11][CH:4]([CH2:3][CH:2]([OH:1])/[CH:12]=[CH:13]/[C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A stirred solution of ethyl (E)-5-hydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-3-oxohept-6-enoate (0.35 g; prepared as described hereinafter in Reference Example 1) in methanol (15 ml) at 0° C. was treated with sodium borohydride (0.02 g). The mixture was stirred for one hour and then a further portion of sodium borohydride (0.05 g) was added and stirring was continued for another period of 30 minutes. The resulting clear yellow solution was poured into water (100 ml), forming a white solid. The mixture was extracted with diethyl ether (3×75 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give ethyl (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoate (0.35 g) in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1[C:32](=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][O:33][CH3:32])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 ml) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloroemthane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was dissolved in tetrahydropyran (2 mL), sodium methoxide (30% in methanol, 0.43 ml, 2.32 mmol) was added and the resulting mixture was stirred for 1 h at ambient temperature. It was diluted with ethyl acetate (20 mL) and washed aqueous ammonium chloride (saturated). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (25 mg, 14%) as a white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]#[CH:14])[CH3:10].[Na].C(O)CCC.O>O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:14]=1)[CH3:10]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#CC(OCC)OCC
Agent: [Na]
Solvent: O
Solvent: CCCCO
Product: CCOC(OCC)c1cn(C[Si](C)(C)C)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stir bar were added (azidomethyl)(trimethyl)silane (1.000 g, 7.740 mmol), 3,3-diethoxyprop-1-yne (0.992 g, 7.740 mmol), freshly made 1.0N sodium asorbate (0.774 ml, 7.740 mmol), and 1.0N Cu2SO4 (0.774 ml, 7.740 mmol) into 30.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.620 g, 81% crude). ES-MS [M+1]+: 258.1 (M+H). This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11](Cl)[C:10]=2[Cl:17])=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1.[Cl:21]C1C=CC=C(Cl)C=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[C:14]([Cl:21])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Product: COCc1nc(N)nc(N)c1-c1c(Cl)cccc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 2 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. 204°-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: OCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CNc2ccccc2)cc1
Yield: 90 %

Procedure:
200 parts of aniline, 108 parts of benzyl alcohol and 10 parts of triphenyl phosphite are heated for 20 hours at 240° C in a stirred autoclave. The autoclave is then let down and the water of reaction which has formed, the excess aniline and the unconverted alcohol are distilled off under reduced pressure. 165 parts of N-benzylaniline, corresponding to a yield of 90% of theory, distil at a boiling point of 125° C/0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37].NCCCCO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37])[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Reactant: CC(O)CCN
Agent: NCCCCO
Product: CC(O)CCNc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1

Procedure:
The compound was prepared from 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea and 4-amino-butan-2-ol as described in example 10 for 4-amino-butan-1-ol instead.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH:33]=O)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH2:33][N:6]2[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]2)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCC1(C(=O)O)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
4-ethylpiperidine-4-carboxylic acid (0.184 g, 1.17 mmol) was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol), Acetic acid (0.19 mL, 3.4 mmol) in Methanol (1.9 mL, 48 mmol) and stirred for 30 min. The reaction was then cooled to 0° C. on an icebath and sodium cyanoborohydride (90.9 mg, 1.4 mmol) was added. The reaction was then allowed to warm to room temperature while stirring overnight. Reaction was then concentrated to about 4-5 mL then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 7 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid as a white solid (2%). ESI-MS: 452 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.75-8.00 (m, 3H), 7.47-7.61 (m, 1H), 7.43 (s, 1H), 7.07-7.28 (m, 1H), 4.44 (m, 3H), 3.29-3.54 (m, 2H), 2.74-3.03 (m, 2H), 2.20 (s, 3H), 1.64-1.98 (m, 3H), 1.02-1.65 (m, 9H), 0.89 (s, 9H), 0.76-0.83 (m, 3H).
Reaction SMILES: N1([CH2:10][NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)C2C=CC=CC=2N=N1.[Cl:17][C:18]([Cl:27])=[C:19]([O:25][CH3:26])[O:20][Si](C)(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:26][O:25][C:19](=[O:20])[C:18]([Cl:27])([Cl:17])[CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(O[Si](C)(C)C)=C(Cl)Cl
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(Cl)(Cl)CNC1CCCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4.3 g (0.02 mole) of benzotriazol-1-ylmethyl-cyclopentyl-amine and 6.4 g (0.030 mole) of (2,2-dichloro-1-methoxy-vinyloxy)-trimethyl-silane in 140 ml of anhydrous dichloromethane was added dropwise 3.7 ml (0.030 mole) of boron trifluride diethyl etherate at 0 degrees. The reaction was stirred at 0 degrees for 1 hour and then at room temperature for 24 hours. The reaction was quenched by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane. The organic layer was washed with saturated sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-85:15) gave 2.4 g of 2,2-dichloro-3-cyclopentylamino-propionic acid methyl ester as a colorless oil.
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42]C(O)=O)[C:37]=2[CH:46]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42][CH2:10][N:11]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)[C:12](=[O:24])[NH:13][C:14]3[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=3)[C:37]=2[CH:46]=1
Reactant: O=C(O)CCc1coc2ccc(Cl)cc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2coc3ccc(Cl)cc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(5-chloro-benzofuran-3-yl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(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>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1OC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(OC2CC2)c1

Procedure:
To a solution of 4-bromo-2-(cyclopropyloxy)benzonitrile (108 mg, 0.45 mmol) in 20 ml of toluene was added LiCl (38 mg, 0.9 mmol), Pd(PPh3)4 (15 mg), allyl tributyltin (180 g, 0.55 mmol), then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered, the filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(cyclopropyloxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]2[CH2:43][CH2:44][CH:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:40][CH2:41]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) was coupled with 4-pyrrolidin-1-yl-piperidine (31 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF at rt for overnight to give the titled compound. MS m/z 639 [M−1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (10.4 g) and (4-chlorophenyl)methanol (10 g) in DMF (50 ml) was added potassium carbonate (14.5 g), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water while the product was precipitated out from the reaction medium. The precipitate was collected by filtration and dried under vacuum to give the title compound (4.8 g) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>C(Cl)Cl>[Br:24][C:25]([CH3:30])([CH3:29])[C:26]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:8][CH2:9][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:13][CH2:14]2)[CH2:11][CH2:12]3)=[CH:6][CH:5]=1)=[O:27]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice water cooled solution of crude methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 16; 961 mg, 3.53 mmol) in DCM (10 mL) was added aluminium chloride (1.4 g, 10.58 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.45 mL, 3.53 mmol). The reaction mixture was allowed to stir at ˜0° C. for ˜40 mins, it was then poured onto ice-water (˜100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 120 g silicyle silica cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc, the product eluting at 10% EtOAc. The mixed fractions were combined and recolumned on a 120 g silica cartridge as described above; to yield the title compound as a white solid, (705 mg 1.67 mmol, 47%). 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.1 g, 79% yield).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17](Cl)=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C(C1C=CC=CC=1C(Cl)=O)(C)(C)C>C(O)C>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17]([NH:37][NH2:38])=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: CC(C)(C)c1ccccc1C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
The 6-(p-tert.butylbenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8 (g), from 34.2 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 25 g of tert.butylbenzoyl chloride. M.P. 157°-160° (decomp., from 95% ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:24])=O)[CH2:20][CH2:19][CH2:18][CH2:17]C1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:22](=[O:24])[CH:21]([CH:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Reactant: Nc1ncc(Cc2ccc(Cl)cc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccc(Cl)cc2)o1)C(c1ccccc1)C1CCCC1
Reaction time: 16 h

Procedure:
5-(4-Chloro-benzyl)-oxazol-2-ylamine (42 mg, 0.20 mmol) and cyclohexyl-phenyl-acetic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added, and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (9.6 mg, 0.023 mmol, 12%). ESI-MS m/z calc. 408.9, found 409.4 (M+1)+ Retention time 3.76 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)COCCOC2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2COCCOC2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-[1,4]-dioxepan-6-ol (6.20 g, 0.028 mol) in CH2Cl2 was added triethylsilane (3.53 g, 0.031 mol) and trifluoroacetic acid (35.1 g, 0.31 mol). The reaction mixture was allowed to stir overnight. The reaction was made basic with K2CO3 solution until pH=10. The organic layer was dried (MgSO4), filtered and evaporated to dryness to give the desired product as a red oil (5.84 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1cnc(-n2nnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ncccn2)C1
Reaction time: 3 h

Procedure:
A solution of 1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (97 mg, 0.48 mmol), 2-chloro-3-(trifluoromethyl)-benzoic acid (118 mg, 0.53 mmol) and Et3N (0.1 ml, 0.72 mmol) in DMF (2.5 ml), was treated with HATU (219 mg, 0.58 mmol) and stirred for 3 h.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[OH:21])[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Product: COC(=O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
57 g (200 mM) of methyl 3-(1-adamantyl)-4-hydroxybenzoate are treated with benzyl bromide under the conditions described in Example 5(a) to lead to 69.5 g (92.4%) of the expected derivative, of melting point 127° C.