Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:3])[NH2:2].Br[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)C>[C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])[CH:8]=1)=[O:6])(=[O:3])[NH2:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2c[nH]c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A solution of 0.10 g (0.223 mmol) of the product from step d), 0.15 g (0.56 mmol) of N-(3-bromopropyl)phthalimide, 0.10 g (0.72 mmol) of K2CO3 and 1.5 ml of DMF. The flask was sealed and heated to 65° C. for 5 hours. The reaction mixture was partitioned between 10 ml of EtOAc and 10 ml of water. The organic phase was collected and the aqueous phase was extracted with an additional 10 ml of EtOAc. The combined organic phases were washed with water and brine. The organic phase was evaporated to give a yellowish solid. The solid was suspended in 20 ml of diethyl ether and stirred for 30 minutes. The precipitate was allowed to settle and the ethereal phase was removed. The residual precipitate was dried in vacuum to give 100 mg (70%) of the sub-title product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN1CCOCC1>C1COCC1>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[CH2:13][NH:12][C:10]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:2][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=1)=[NH:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(CNC(=O)c2ccccc2)cs1

Procedure:
Reaction of 50 mg (0.16 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, with 24.2 mg benzoylchloride in 5 ml THF with addition of 230 mg polymer-bound NMM (1.7 mmol/g; Argonaut) and chromatography of the crude product on silica gel dichloromethane/methanol 0-2%) yielded 20 mg; ESI-MS [M+H+]=426.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:40]=[C:41](CO)[CH:42]=[CH:43][CH:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([O:38][CH3:37])[CH:44]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(CO)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(COC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)c1
Yield: 90.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methoxyphenyl)methanol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (136 mg, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:12]1[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: NCCCCCO
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Reaction of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone with 5-aminopentanol at 170°-180° gave 2-(5-hyroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which was isolated as the dihydrochloride salt m.p. 215°-217°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cl)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (12.0 g, 45.6 mmol) was taken in neat oxalyl chloride (30 ml), 0.2 mL of DMF was added and the mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. Then the reaction mixture was concentrated under reduced pressure to provide (S)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXXIII) (12.66 g) which was directly used in the next reaction.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([NH:21][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[S:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2cccc(OCc3ccccc3)c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(OCc4ccccc4)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of 3.0 g of 4-(3-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 1.8 g of p-toluenesulfonyl chloride was stirred for 2 hours with 12 ml of pyridine. The resulting, red colored suspension was poured into 100 ml of 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 120 ml of ethanol and 120 ml of 2N sodium hydroxide solution. After the addition of 2.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was chromatographed on 300 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated and yielded 2.2 g of N-[4-(3-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as a colorless, amorphous solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:30]=[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:32]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:34]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:28][C:29]2[CH:30]=[C:31]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:32]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:34]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc(-c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CH2Cl2 solution (0.05 M) of trans-tert-butyl 3-[(cyclopropyl{[5-(3-methoxypropyl)biphenyl-3-yl]methyl}amino)carbonyl]-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-1-carboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 45 min. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 514. Human Renin IC50 (buffer): 15 nM. Human Renin IC50 (plasma): 81 nM.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:12].BrCC1C(Cl)=CC2[CH:19]=[CH:20][O:21]C=2C=1.C[N+]1([O-])CC[O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:12][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:10][CH:9]([O:21][CH2:20][CH3:19])[O:29][CH2:28][CH3:27])=[CH:8][C:3]=1[CH3:2]
Reactant: Clc1cc2ccoc2cc1CBr
Reactant: Clc1ccc2occc2c1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOC(COc1ccc(Cl)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-bromomethyl-5-chloro-benzofuran mixture with 6-bromomethyl-5-chloro-benzofuran (30.54 g) in dry acetonitrile (80 ml) was added dropwise to a mixture of N-methylmorpholine-N-oxide (29.14 g) and 4 Å molecular sieves in dry acetonitrile (100 ml) at 100 under nitrogen. The mixture was stirred at room temperature for 5 h, filtered through hyflo and the filtrate evaporated. The residue was triturated under ether (100 ml) and filtered. The filtrate was evaporated and the residue recrystalised from cyciohexane to give the title compound as a pale yellow solid (10.95 g)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[N:26][CH:25]=[N:24]1>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: NCCCn1cncn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCCn1cncn1)c1ccc(I)cc1
Reaction time: 3 h

Procedure:
A mixture of about 2.48 g of 4-iodobenzoic acid, about 1.62 g of 1,1'-carbonyldiimidazole and about 30 ml oftetrahydrofuran was stirred for about 3 hours, then about 1.3 ml of 1H-1,2,4-triazole-1-propanamine was added and stirring was continued overnight. The mixture was heated for about 2 hours, about 5 ml of water was added, heating was continued for an additional hour then the mixture was concentrated to a residue. Methylene chloride and about 10 ml of approximately 1N sodium hydroxide were added. The organic layer was separated, washed with water, dried and concentrated, giving about 2.7 g of the desired product as a white solid, mp 132°-134° C.
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2S[CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:25][CH:24]=1)=[O:22])C(=O)[O-])(C)C.[C:41](O)([C:43](F)(F)F)=O>C(Cl)Cl>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][O:33][C:31](=[O:32])[NH:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:21]([NH:20][C:10]3[CH:11]=[C:12]([C:15]4[CH:43]=[CH:41][CH:17]=[CH:18][CH:19]=4)[CH:13]=[CH:14][C:9]=3[NH2:5])=[O:22])=[CH:24][CH:25]=2)[CH:36]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Reaction time: 1 h

Procedure:
1,1-dimethylethyl[2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamate (10.5 g, 19 mmol) was taken up in DCM (208 mL)/TFA (41.7 mL). After 1 hour, the solvent was removed in vacuo, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give pyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate as a tan solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.69 (s, 1H), 8.57 (s, 1H), 8.51 (dd, J=4.8 and 1.8 Hz, 1H), 7.94 (m, 3H), 7.77 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.37 (m, 5H), 7.31 (dd, J=8.4 and 1.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 5.08 (br s, 4H), 4.26 (d, J=6.0 Hz, 2H). MS: cal'd 453 (MH+), exp 453 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[Br:19]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([Br:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(Br)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 62.1 %

Procedure:
This compound was prepared in the manner of Example 1 with 7.6 grams (0.027 mole—1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 10.0 grams (0.056 mole—2.1 equiv.) of N-bromosuccinimide, and 50 mL of concentrated sulfuric acid (% wt/vol. triazole to solvent—15.2%) as reagents. A yield of 6.06 grams of 92.4% pure 1-(4-chloro-2-fluoro-5-bromophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (62.1% yield) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][N:20]=2)[N:17]=1)=O.Cl.[NH2:26][OH:27].[N:28]1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O.C1(C)C=CC=CC=1.CCO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][N:20]=3)[N:17]=2)=[N:28][O:27][N:26]=1
Reactant: NO
Reactant: c1ccncc1
Reactant: CC(C)c1nnc2ccc(C(=O)C(=O)c3ccc(F)cc3F)nn12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1nnc2ccc(-c3nonc3-c3ccc(F)cc3F)nn12
Temperature: 90 °C
Yield: 18 %

Procedure:
A 50 mL round bottomed flask was charged with 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethane-1,2-dione (0.300 g, 0.908 mmol, Preparation #M.1), hydroxylamine hydrochloride (0.631 g, 9.08 mmol) and EtOH (5 mL). The resulting mixture was treated with pyridine (3.67 mL, 45.4 mmol) and was then heated to about 90° C. for about 7 h. The mixture was cooled to ambient temperature, diluted with EtOAc (10 mL), washed with 1N HCl (10 mL) and water (10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to afford a yellow residue. To the residue was added triphenylphosphine (0.328 g, 1.25 mmol) and toluene (5 mL). The mixture was cooled to about 0° C. and DIAD (0.243 mL, 1.25 mmol) was added to give a solution which was heated to about reflux for about 1 h. The solution was cooled to ambient temperature, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The organics were separated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel with MeOH/DCM (0-5% gradient) followed by RP-HPLC (Table 1, Method n) to afford the title compound (0.056 g, 20%) as a yellow solid. LC/MS (Table 1, Method g) Rt=2.83 min; MS m/z 343 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[N:18]=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][C:14]=3[CH2:13]2)=[O:11])[CH2:3]1.[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>>[O:26]1[CH2:31][CH2:30][CH:29]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:21][CH2:20][C:19]4[N:18]=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][C:14]=4[CH2:13]3)=[O:11])[CH2:3]2)[CH2:28][CH2:27]1
Reactant: O=C1CCOCC1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)[C@@]12CCO[C@@H]1C[C@@H](NC1CCOCC1)C2

Procedure:
The title compound was prepared from reaction of the product of Example 1, Step G and tetrahydro-4H-pyran-4-one following the procedure described in Example 1, Step H. 1H NMR (CHLOROFORM-d) δ: 8.72 (br. s., 1H), 7.70 (br. s., 1H), 5.04 (d, J=4.6 Hz, 1H), 4.78 (br. s., 2H), 3.95 (s, 2H), 3.97 (s, 3H), 3.53-3.75 (m, 2H), 3.28-3.49 (m, 2H), 3.14 (br. s., 2H), 2.62-2.81 (m, 1H), 2.29 (dd, J=12.8, 5.5 Hz, 3H), 1.99-2.17 (m, 1H), 1.60-1.92 (m, 3H), 1.18-1.57 (m, 5H). Calculated for C22H28F3N3O3: 440.2 (M+1). found: 440.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[C:12]([C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([Cl:21])[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].[CH2:22](OCC)[CH3:23]>C(O)C>[ClH:21].[NH2:2][C@H:3]([C:8]1[CH:13]=[C:12]([C:14]([CH3:19])([CH3:20])[C:15]([F:16])([F:17])[F:18])[CH:11]=[C:10]([Cl:21])[CH:9]=1)[CH2:4][C:5]([O:7][CH2:22][CH3:23])=[O:6]
Reactant: CCOCC
Reactant: CC(C)(c1cc(Cl)cc([C@@H](N)CC(=O)O)c1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C(C)(C)C(F)(F)F)c1

Procedure:
Absolute ethanol saturated with anhydrous HCl gas (10 mL) was added to a suspension of (S)-3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)propanoic acid (from step A above) (252.8 mg, 0.816 mmol) in absolute ethyl alcohol (5 mL) and the reaction mixture was heated at reflux for 4 h to give a colorless solution. The solvent was removed in vacuo to give a colorless gummy solid. The solid was slurried a couple of times with diethyl ether (2×5 mL). After the solvent was decanted off, the residue was dried in vacuo to give the desired (S)-ethyl 3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)propanoate hydrochloride salt as a cream foamy solid (293.76 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 338 (35ClM+H), m/z 340 (37ClM+H), m/z 360 (35ClM+Na) and m/z 362 (37ClM+Na); Calcd for C15H19ClF3NO2: 337.77.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:16]1[C:20]([CH3:21])=[C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:18]([CH3:33])=[N:17]1)[CH3:15]>>[CH2:14]([N:16]1[C:20]([CH3:21])=[C:19]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[C:18]([CH3:33])=[N:17]1)[CH3:15]
Reactant: CCn1nc(C)c(CNc2ccc(C(C)C)cc2)c1C
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCn1nc(C)c(CN(C(=O)C2CCCc3ccccc32)c2ccc(C(C)C)cc2)c1C
Yield: 30.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.65 g) as starting materials, N-[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. Oxalic acid was added to this compound. By recrystallization from ethyl acetate, N-[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide ½ oxalate ½ hydrate (0.03 g) was obtained. melting point: 142-143° C.
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S(=O)(=O)(O)O.[CH3:31]O>>[C:1]([O:25][CH3:31])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CO
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reaction time: 1 h
Yield: 74 %

Procedure:
10,12- Tricosadiynoic acid (3.0 g, 0.0084 mol), methanol (15 ml) and concentrated sulfuric acid (0.8 ml) were heated to reflux and stirred for 1 hour. The cooled mixture was taken up in either (40 ml) and washed with 10% NaHCO3 (20 ml) and water (20 ml), and the organic phase was dried (MgSO4). Evaporation of the solvent gave 2.68 g (74%) of the title compound. 1H NMR (60 MHz, CDCl3): δ 0.98 (m, 3H, CH3CH2), 1.28 (m, 28H, CH2), 2.25 (m, 6H, CH2), 3.70 (s, 3H, CH2O).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([F:32])[CH:34]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)cccc23)c1
Yield: 60 %

Procedure:
N-(tert-Butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (1.00 g, 2.21 mmol) in 3-fluoroaniline (2.94 g, 26.5 mmol) was heated in a sealed tube at 100° C. for 12 h. On cooling, the volatile components were removed under reduced pressure and the resulting residue was purified by combiflash (REDISEP®, silica gel, 24 g, 60% EtOAc/hexanes) to obtain N-(tert-butyl)-5-(4-((3-fluorophenyl)amino)-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.70 g, 60%) as a brown solid. LCMS (Condition 11): retention time 1.20 min, [M+1]=528.4. 1H NMR (400 MHz, DMSO-d6) δ 1.94 (s, 9 H), 6.50 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 6.76 (td, J=2.5 Hz, J=8.4 Hz, 1 H), 7.19-7.25 (m, 2 H), 7.53-7.66 (m, 6 H), 7.88-7.93 (m, 3 H), 8.05 (dd, J=6.8 Hz, J=8.4 Hz, 1 H), 8.54 (t, J=2.0 Hz, 1 H), 9.15 (d, J=2.0 Hz, 1 H), 9.16 (d, J=2.0 Hz, 1 H).