Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCCCC=1.O1CCCC1.B.[CH2:13]([N:20]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[C:36]([O:43]C)=[N:37][CH:38]=[C:39]([C:41]#[CH:42])[CH:40]=1)[C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:45].[Na+].[OH:47]O.Cl>C1COCC1.CO>[C:21]([N:20]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH2:41][C:42]([OH:47])=[O:45])[CH:38]=[N:37][C:36]=1[OH:43])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:23])[CH3:22]
Reactant: [OH-]
Reactant: OO
Reactant: C#Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cnc1O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To cyclohexene (0.20 mL, 1.98 mmol) at room temperature was added borane tetrahydrofuran complex (1M in THF; 1.01 mL, 1.01 mmol), and the reaction was stirred for 45 minutes. N-Benzyl-N-[2-(5-ethynyl-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide (0.126 g, 0.29 mmol) in THF (2 mL) was added dropwise, and the reaction was stirred for 2 hours at room temperature. The mixture was cooled to 0° C., and MeOH (1 mL) and 1N aqueous NaOH (1.01 mL, 1.01 mmol) were added, followed by hydrogen peroxide (30%; 0.31 mL, 3.00 mmol), and the reaction was stirred for 1 hour at 0° C. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by preparative HPLC to give (5-{2-[(N-Acetyl-N-benzyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-hydroxy-pyridin-3-yl)-acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8]([CH3:34])([C:10]12[CH2:19][C:14]3([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:15][CH:16]([CH2:18][C:12]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9].C(N(CC)CC)C.C1COCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][C:14]3([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:15][CH:16]([CH2:18][C:12]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:34])[CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COCCOCOC12CC3CC(OCOCCOC)(C1)CC(C(C)(C)O)(C3)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(OCOCCOC)(CC(OCOCCOC)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A total of 30 mmole of methacrylic chloride was added dropwise to a mixture of 20 mmole of the above-prepared α,α-dimethyl-3,5-bis(2-methoxyethoxymethoxy)-1-adamantanemethanol, 40 mmole of triethylamine, and 80 ml of THF, over about 30 minutes. The resulting mixture was stirred at room temperature for 6 hours after the completion of addition. Water was added to the reaction mixture, and the resulting mixture was then extracted with ethyl acetate, the organic layer was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 1-(1-methacryloyloxy-1-methylethyl)-3,5-bis(2-methoxyethoxymethoxy)adamantane.
Reaction SMILES: [Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(O)CCC>[Cl:1][C:2]1[S:21][C:5]2[N:6]3[C:22]([CH3:23])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1
Reactant: CC(=O)NN
Reactant: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21
Solvent: CCCCO
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1[N+](=O)[O-])=NC2

Procedure:
0.2 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione are heated to reflux for 5 hours under a nitrogen atmosphere with 0.2 g of acetic acid hydrazide in 30 ml of n-butanol. After evaporation of the solvent, the product is taken up in methylene chloride and extracted several times with 1-N hydrochloric acid, the organic phase being treated portionwise with ether such that it comes to the surface in the separating funnel. After neutralization of the aqueous phase with sodium bicarbonate, the mixture is extracted with methylene chloride, the solvent evaporated after drying over sodium sulphate and the residue made into a paste with ethyl acetate. The resulting crystals are recrystallized from ethyl acetate containing active carbon to give colorless crystals of 2-chloro-9-methyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 210°-212° C.
Reaction SMILES: C[O:2][C:3](=[O:7])[CH2:4][CH2:5]Br.[CH3:8][O:9][C:10]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:44]([O:45][CH3:46])=[CH:43][C:42]([O:47][CH3:48])=[CH:41][C:40]=1[O:49][CH3:50])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH2:36])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1>>[CH3:58][O:57][C:51]1[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=[C:10]([O:9][CH3:8])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:40]([O:49][CH3:50])=[CH:41][C:42]([O:47][CH3:48])=[CH:43][C:44]=1[O:45][CH3:46])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][CH2:5][CH2:4][C:3]([OH:7])=[O:2])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][CH2:5][CH2:4][C:3]([OH:2])=[O:7])[CH:16]=1
Reactant: COC(=O)CCBr
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NCCC(=O)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NCCC(=O)O)c2)c(OC)c1

Procedure:
A solution of methyl-3-bromopropionate (40 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method B. The product obtained was purified by recrystallization from acetone. (m.p. 156-158° C.)
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[O:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[CH:7][C:6]=1[CH3:29])C.C1COCC1.O.[OH-].[K+]>CO>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]([CH3:28])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([CH3:29])[CH:7]=3)=[CH:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 94.7 %

Procedure:
0.27 g of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) was stirred in a mixture of 5 ml of methanol, 5 ml of THF and 1 ml of water. To this solution 0.2 g KOH was added and the mixture was stirred for 5 days at ambient temperature. The solvents were then evaporated, the residue was diluted with water and acidified with 1N HCl. The solid that precipitated was isolated by filtration and dried to give 0.240 g (95%,) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (IIa) as a pale solid. 1H-NMR (CDCl3, δ in ppm): 8.05 (d, 1H), 7.26-7.44 (m, 5H), 5.46 (s, 1H), 3.00 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.[CH2:16]([CH:18]1[CH:22]([C:23]2[N:27]3[C:28]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=4[N:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:21][C:20](=[O:43])[CH2:19]1)[CH3:17]>C1COCC1>[CH2:16]([CH:18]1[CH:22]([C:23]2[N:27]3[C:28]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:21][C:20]([CH2:1][S:2]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)(=[O:4])=[O:3])([OH:43])[CH2:19]1)[CH3:17]
Reactant: CS(=O)(=O)N1CCOCC1
Reactant: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1CC(O)(CS(=O)(=O)N2CCOCC2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a solution of 4-(methylsulfonyl)morpholine (0.217 g, 1.314 mmol, Preparation #41) in THF (4 mL) at about 0° C. was added n-BuLi (2.5 M in hexanes, 0.53 mL, 1.3 mmol). The reaction mixture was stirred at about 0° C. for about 1 h. The resulting solution was added dropwise to a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.350 g, 0.876 mmol, Example #35 Step G) in THF (4 mL) at about 0° C. The reaction mixture was maintained at about 4° C. in a refrigerator for about 48 h. The reaction mixture was partitioned between water (5 mL) and DCM (5 mL) The layers were separated and the aqueous solution was extracted with DCM (2×5 mL). The combined organic extracts were concd under reduced pressure. The product was purified by silica gel chromatography eluting with a gradient of 0-2% MeOH/DCM, then by RP-HPLC (Table 1, Method 1) to give 3-ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.17 g, 34%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.32 & 2.42 min; MS m/z: 565 (M+H)+.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]#[CH:3])=[CH:6][CH:7]=1)#[N:12]
Reactant: CC(C)(O)C#Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#Cc1ccc(C#N)cc1
Reaction time: 4 h
Yield: 61.4 %

Procedure:
3-Methyl-1-(4'-cyanophenyl)-1-butyne-3-ol (23.5 g) was dissolved in toluene (250 ml) under nitrogen atmosphere, and then sodium hydride (1.6 g) was added thereto, followed by stirring at 80° to 90° C. for 4 hours. The reaction solution was poured into water (300 ml), and then extracted with chloroform, followed by washing with water 3 times. After distilling off toluene and chloroform, the resultant was recrystallized from methanol to give 4-cyanophenylacetylene (9.9 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@@:24]2([CH:40]=[O:41])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:42][CH3:43])=[CH:20][C:21]=1[CH2:22][CH2:23]2)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[Si:33]([O:32][C@H:28]1[CH2:27][CH2:26][C@H:25]2[C@@:24]3([CH:40]=[O:41])[C@H:15]([C@@H:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:31][C@:29]12[CH3:30])[C:16]1[CH:17]=[CH:18][C:19]([O:42][CH3:43])=[CH:20][C:21]=1[CH2:22][CH2:23]3)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@]1(C=O)[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)C[C@H](CCCCCO)[C@H]21
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A solution of 14.36 g of tetraene 6 in 400 ml of tetrahydrofuran/methanol (3:1) is mixed with 2.8 g of palladium (10% on carbon) and stirred under a hydrogen atmosphere (100 bar) for two days at room temperature. This reaction is repeated twice. For working-up, it is filtered on Celite and concentrated by evaporation in a vacuum. The residue is purified by column chromatography (cyclohexane/ethyl acetate) and yields 8.25 g of 7 as a colorless foam (GC-MS: m/z theor.: 514, pract.: 514).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1F)[CH3:2].C(N(C(C)C)CC)(C)C.C[N:26]1C(=O)[CH2:29][CH2:28][CH2:27]1>>[N+:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:26]3[C@H:2]([CH2:1][O:3][C:4](=[O:15])[C:5]=2[CH:10]=1)[CH2:29][CH2:28][CH2:27]3)([O-:13])=[O:12]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@@H]2CCCN2c2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
By adopting a similar procedure as described in “Mueller, W; Stauss, U.; Forschungsinst, W.; Bern, S. Helvetica Chimica Acta 1982, 65, 2118.” (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was prepared as follows. A mixture of 2-fluoro-5-nitro-benzoic acid ethyl ester (1.16 g, 5.44 mmol), S-prolinol (638 mg, 6.31 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) in dry NMP (20 mL) was stirred at 100° C. for 3 h. Solvent was removed and the mixture was partition between EtOAc and water. Organic layer was extracted two more times with EtOAc. Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. The product, (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was obtained as a solid (1.08 g, 80%). 12b) (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one (1 g, 4 mol) was taken in MeOH (50 mL) and was cooled to 0° C. Sodium borohydride (1 g, 26.43 mmol, 300 mg was added in portion in the first phase, 700 mg after 4 h at RT) was added and the cooling bath was removed. After stirring overnight at RT, the mixture was quenched with water. The mixture was treated with 1N Na2CO3 solution (100 mL) and dichloromethane (100 mL). The mixture was extracted from dichloromethane (twice). Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. A gum was obtained which was taken in 50% H2SO4 (20 mL). The mixture was stirred at 120° C. for 45 minutes. The mixture was cooled to RT and was neutralized with NaHCO3 solution and was extracted from EtOAc. Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. The crude product was purified by flash chromatography (hexane:EtOAc 3:1). The product (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was obtained as an yellow solid (451 mg, 48% in two steps); 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=9.1 Hz, 1H), 8.00 (s, 1H), 6.75 (d, J=9.09 Hz, 1H0, 5.14 (d, J=14.14 Hz, 1H), 4.36 (d, J=13.89 Hz, 1H), 5.14 (d, J=14.14 Hz, 1H0, 4.36 (d, J=13.89 Hz, 1H), 4.07 (m, 1H0, 3.93 (m, 1H), 3.41 (m, 1H), 3.35-3.31 (2m, 2H), 2.17-1.89 (2m, 3H), 1.57 (m, 1H); MS (m/e) 235 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:5])[CH3:2].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][CH2:13][N:14]([CH3:15])[CH3:16])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]=[CH:12][CH2:13][N:14]([CH3:15])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCCN(C)C)CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1CCCC1N=CCN(C)C
Product: CCOC(=O)C1CCCC1NCCN(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 167.4 %

Procedure:
A solution of 2-(2-dimethylamino-ethylamino)-cyclopent-1-enecarboxylic acid ethyl ester (2.18 g, 9.63 mmol) in ethanol (100 mL) was treated with glacial acetic acid (10 drops), sodium cyanoborohydride (1.21 g, 19.26 mmol) and stirred for 16 h at 50° C. The reaction was diluted with ethyl acetate (100 mL) and washed twice with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to afford the desired product, 2-(2-dimethylamino-ethylideneamino)-cyclopentanecarboxylic acid ethyl ester (1.84 g, 8.06 mmol, 83.7%), as a light yellow oil. LC-MS (ESI) calcd for C12H24N2O2 228.18, found 229.3 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:24]#[N:25].[Na+].C1(C)C=CC=CC=1>CN(C=O)C.O>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18][C:24]#[N:25])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CBr)cc3Cl)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CC#N)cc3Cl)cc12

Procedure:
Analogously to the procedure of Example VIII, 1.0 g (2.42 mmol) of benzyl bromide from Example XVIII is reacted with 0.15 g (3.03 mmol) of sodium cyanide in DMF/H2O (10:1) at 50° C. in 60 min. After isolation of the crude product (distilling off DMF and quenching with ethyl acetate/water), chromatography is carried out on silica gel 60 by means of toluene.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1.CN(C=O)C.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C([Cl:37])=O>C(Cl)Cl>[Cl:37][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[N:12]=1
Reactant: Oc1nc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of 2,6-bis(trifluoromethyl)quinazolin-4-ol (200 mg, 0.666 mmol, prepared in the previous step), DMF (0.01 mL, 0.129 mmol) and diisopropylethylamine (0.17 mL, 0.986 mmol) suspended in dry DCM (10 mL) and treated dropwise with oxalyl chloride (0.11 mL, 1.26 mmol) under argon. After the addition, the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the reaction was quenched by the cautious addition of potassium phosphate dibasic solution (20% w/w) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to yield the product as a white solid.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:47]=[CH:46][C:34]([C:35]([NH:37][C@@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([OH:41])=O)=[O:36])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:32]=[CH:33][C:34]([C:35]([NH:37][C@H:38]([C:39]([N:4]([CH3:5])[CH3:1])=[O:41])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])=[CH:46][CH:47]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of (2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoic acid (14 mg, 0.026 mmol), dimethylamine (0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RT overnight. The residue was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=555.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[CH:16][CH:15]=2)=[C:5]([C:11](O)=O)[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].Cl.[CH3:35]N(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[CH:16][CH:15]=2)=[C:5]([C:11]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH2:35])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1c(C#N)c(-c2ccc(OCc3ccccc3F)cc2)c(C(=O)O)n1C
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(NS(C)(=O)=O)c1c(-c2ccc(OCc3ccccc3F)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
Mix together 4-cyano-5-ethyl-3-[4-(2-fluoro-benzyloxy)-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid (100 mg, 0.26 mmol, prepared in example A-171), methanesulfonamide (27 mg, 1.1 Eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 1.2 Eq.), and 4-dimethylaminopyridine (35 mg, 1.1 Eq.) in methylene chloride (8 mL) and stir overnight at room temperature under a nitrogen atmosphere. Pour the mixture into 1N HCl and extract the desired amide into methylene chloride. Separate layers, wash the organic layer once with water, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced vacuum to provide 107 mg as an oil. Purify the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride/methanol 19:1 to provide 71 mg of the title compound as a tan foam: Mass spectrum (m/e): 456.2 (M*+1): (Bruker 300) 1H NMR (DMSO) 8.70-8.75 (1H, s), 7.50-7.65 (2H, d), 7.00-7.40 (6H, m), 5.05-5.20 (2H, s), 3.65-3.75 (3H, s), 3.45-3.60 (3H, s), 2.56-2.76 (2H, dd), 1.00-1.10 (3H, t).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:32][CH:31]([C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C1(C(O)CCCCc2ccccc2)CCCC1
Temperature: -40 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Diisopropylamine (17.5 mL, 124 mmol) is dissolved in THF (80 mL), cooled to -40° C. and 2.38 M n-butyl lithium in hexanes (52 mL, 124 mmol) is added over 5 minutes. The reaction is allowed to warm to 0° C. and cyclopentanecarboxylic acid (6.7 mL, 62 mmol) in THF (60 mL) is added over 5 minutes. The reaction is heated at 40° C. for 1 hour. The reaction is cooled to -78° C. and 5-phenylpentanal (10 g, 62 mmol) in THF (20 mL) is added dropwise over 15 minutes. The cooling bath is removed and the reaction is allowed to stir at room temperature overnight. The reaction is acidified with 2 N HCl (120 mL) and the organics are removed in vacuo. The resulting aqueous mixture is extracted with CH2Cl2 (200 mL) and this organic layer is dried over MgSO4. The solution is concentrated in vacuo, and the resulting residue is purified by column chromatography (silica, 50% ether in petroleum ether) to yield 1-(1-hydroxy-5-phenylpentyl)cyclopentanecarboxylic acid (13.1 g, 77%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.19-7.15 (m, 3H), 3.53-3.46 (m, 1H), 2.64-2.58 (m, 2H), 2.20-2.13 (m, 1H), 2.07-1.99 (m, 1H), 1.95-1.73 (m, 1H), 1.67-1.49 (m, 8H), 1.44-1.32 (m, 3H); MS (EI) m/e 276 (M+).