Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:26][C:25]3[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(C=Nc2[nH]nc(Nc3cccc(Cl)c3)c2C(N)=O)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 4-methylsulphonyl benzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[N:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7]1)=[O:5].C([O-])(=O)C.[K+]>CN(C=O)C.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>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]3[C:4](=[O:5])[C:3]4[C:19]([C:7]3=[C:8]([CH:17]=[O:18])[C:9]=2[N:10]=1)=[CH:20][CH:21]=[CH:22][CH:2]=4
Reactant: COc1ccc2c(n1)c(C=O)cn2C(=O)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)c(C=O)c1n2C(=O)c2ccccc2-1

Procedure:
Under an argon atmosphere, 0.49 mmol of the compound obtained in Step B, 0.2 mmol of tetrakis(triphenylphosphine)palladium(0) and 0.49 mmol of potassium acetate in 15 ml of DMF are heated at 140° C. for 3 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated, and the residue is purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=2)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)C(O)=O.[OH2:20]>>[F:18][CH:15]1[C:14]([CH3:19])=[CH:13][C:12]2[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][CH:4]=3)[CH2:1][C:17]=2[C:16]1=[O:20]
Reactant: O
Reactant: Cc1cc(-c2c(C)cc(F)cc2C(=O)O)ccc1F
Product: CC1=CC2=C(Cc3cc(F)ccc32)C(=O)C1F
Temperature: 180 °C
Yield: 33 %

Procedure:
A stirred mixture of methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoic acid (6.5 g, 26.2 mmol) and polyphosphoric acid (30 g) was heated at 180° C. for 2 h. After the mixture had cooled to 80° C., it was poured into water (200 mL), and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, treated with charcoal, and concentrated. Chromatography on silica gel using 20% toluene in hexane provided 2 g (33%) of the desired ketone.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([CH2:13][CH3:14])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([C:48]1[CH:49]=[C:50]([CH:55]=[C:56]([CH3:59])[C:57]=1[OH:58])[C:51]([NH:53]O)=[NH:52])[CH3:47]>C(Cl)Cl>[CH2:2]([C:4]1[CH:12]=[C:8]([C:9]2[O:11][N:53]=[C:51]([C:50]3[CH:55]=[C:56]([CH3:59])[C:57]([OH:58])=[C:48]([CH2:46][CH3:47])[CH:49]=3)[N:52]=2)[CH:7]=[N:6][C:5]=1[CH2:13][CH3:14])[CH3:3]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCc1cc(C(=O)O)cnc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
To a solution of 5,6-diethyl-nicotinic acid hydrochloride (920 mg, 4.3 mmol) and Hünig's base (2.76 g, 21 mmol) in DCM (50 mL) is added TBTU (1.785 g, 5.55 mmol) and the mixture is stirred at rt for 5 min. 3-Ethyl-4,N-dihydroxy-5-methyl-benzamidine (1.14 g, 4.7 mmol) is added and the mixture stirred for 0.5 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 5,6-diethyl-nicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min) is dissolved in dioxane (50 mL) and heated to 100° C. for 18 h. The solvent is evaporated and the crude product is purified by FC on silica gel eluting with heptane:EA 10:1 to give 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (0.42 g) as a solid; LC-MS: tR=1.03 min, [M+1]+=338.09.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17]O[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 18) (0.043 g, 0.173 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.089 g, 0.207 mmol), PdCl2(dppf)-CH2Cl2Adduct (1.41 mg, 1.73 μmol) and 1 N aq. sodium bicarbonate (0.346 ml, 0.346 mmol) in dioxane (0.864 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclo pentyl amino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.046 g, 52%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.65-1.89 (6H, m), 2.18-2.25 (2H, m), 4.61-4.66 (1H, m), 6.93-7.01 (2H, m), 7.22 (1H, d, J=7.6 Hz), 7.85-7.90 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.82 (1H, d, J=2.0 Hz). m/z=517.2 [M+1]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C:45](=[NH:62])[NH:46][CH2:47][CH2:48][CH2:49][C@@H:50]([C:59]([OH:61])=O)[NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:77])[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>CN(C=O)C>[CH2:70]([O:69][C:68](=[O:77])[NH:67][CH2:66][CH2:65][NH:64][C:59](=[O:61])[C@H:50]([CH2:49][CH2:48][CH2:47][NH:46][C:45]([NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])=[NH:62])[NH:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
419.3 mg (1.1 mmol) of HATU and 258.5 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 408.4 mg (1 mmol) of N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 253.76 mg (1.1 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[K+]>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNC1
Agent: [K+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Yield: 81 %

Procedure:
A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0° C. and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0° C. and then extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacua. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacuo to give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil. Rf=0.11 in 50/50 hexanes/ethyl acetate Mass Spectrum (FD+): M+221; IR (CHCl3, cm-1): 913, 977, 993, 1100, 1117, 1175, 1236, 1360, 1427, 1454, 1498, 1694, 2884, 2954, 3013, 3020, 3436 (broad), 3610; UV (C2H5OH) λmax =205 (ε=9112), 264 (ε=142); 1H NMR (300 MHz, CDC13) δ: 1.91-2.05 (m-, 2H); 3.00 (broad s, 1H); 3.39-3.61 (m, 4H); 4.41 (s, 1H); 5.12 (s, 2H); 7.30-7.43 (m, 5H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[N+:15]([O-:18])([OH:17])=[O:16]>C(O)C>[N+:15]([O-:18])([OH:17])=[O:16].[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([NH:9][C:2]([NH2:3])=[NH:1])[CH:10]=[CH:11][CH:12]=1
Reactant: N#CN
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1cccc(C(F)(F)F)c1

Procedure:
6.3 g (150 mmol) of cyanamide (50% in water) are added to a suspension of 16.1 g (100 mmol) of 3-trifluoromethyl-aniline in 35 ml of ethanol. 7.0 ml of nitric acid (65%, 0.1 mol) are then added to the brown solution and the reaction mixture is heated for 20 h under RF. It is then cooled to 0° and filtered, and the material retained on the filter is washed with ethanol and dried at 60° under HV to give 3-trifluoromethyl-phenylguanidine nitrate; 1H-NMR (dimethyl sulfoxide): 7.6 (7H,m), 9.9 (1H,br,s).
Reaction SMILES: COC1[N:8]=CC2N(C3SC(C(OC)=O)=C(OCC4C=CC=CC=4C(F)(F)F)C=3)C=NC=2C=1.[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([O:51]C)=O)=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:64])([F:63])[F:62])[CH:45]=3)[C:37]=2[CH:36]=1.N>CO>[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([NH2:8])=[O:51])=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:62])([F:63])[F:64])[CH:45]=3)[C:37]=2[CH:36]=1
Reactant: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1OCc1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1OCc1ccccc1C(F)(F)F
Agent: N
Solvent: CO
Product: COc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A suspension of 140 mg of an isomeric mixture of methyl 5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compounds B6a and B6b) in 20 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 130° C. for 5 h in the microwave cavity. The reaction mixture was concentrated to dryness, the residue dissolved in 4 ml acetonitrile and 3 ml acidic buffer (KH2PO4, pH=2) and the isomers were separated and purified by preparative HPLC (acidic buffer/acetonitrile, 7/3 (v/v)). The acetonitrile was removed under vacuum and the aqueous solution was treated with NH4OH until pH 8-9 was reached. The aqueous solution was extracted with dichloromethane three times and the combined organic layers were dried and concentrated to dryness under vacuum to yield the title compound.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 13 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using isopropylamine instead of morpholine, to the title compound (14 mg, 13%), which was obtained as a colorless oil. MS: m/e=341.3 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH:11]1([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1>S(=O)(=O)(O)O.O1CCOCC1>[CH:11]1([N:14]2[CH2:19][CH2:18][C:17]3[NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][C:7]=4[C:16]=3[CH2:15]2)[CH2:13][CH2:12]1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCN(C2CC2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A solution of (4-methylphenyl)hydrazine hydrochloride (1.5 g, 0.00948 mol) and 1-cyclopropylpiperidin-4-one (1.3 g, 0.00948 mol) in 7% sulfuric acid in dioxane (20 mL) was heated at 80° C. for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and the dioxane layer was decanted. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated affording crude material, which was purified by silica gel column chromatography (2% MeOH:DCM) to yield 2-cyclopropyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.4 g, 66% yield).
Reaction SMILES: [ClH:1].C(OC(=O)[N:8](C1C=CC(C#N)=CC=1)[CH2:9][C:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)(C)(C)C.O1[CH2:41][CH2:40]OCC1>>[ClH:1].[NH2:8][CH:9]([C:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:41]1[CH:40]=[CH:14][C:10]([C:9]#[N:8])=[CH:11][CH:12]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1
Agent: Cl
Product: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 M, 29.3 mL, 117 mmol) is added to a mixture of tert-butyl(4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methylcarbamate (intermediate 12, 6.92 g, 14.7 mmol) in 1,4-dioxane (30 mL), and the mixture is stirred at room temperature for 2 h. All volatiles are removed under reduced pressure, and the residue is treated with tert-butyl methyl ether (50 mL). The precipitate is filtered, washed with tert-butyl methyl ether and dried. Yield: 6.10 g. ESI mass spectrum: [M+H]+=372; Retention time HPLC: 0.62 min (X011_S02).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])[CH:2]([CH3:4])[CH3:3].B(F)(F)F.[CH3:17][CH2:18][O:19]CC.C(O)(=O)C.CC([O-])=O.[Na+]>>[OH:11][C:8]1[CH:7]=[C:6]([OH:12])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=1[C:18](=[O:19])[CH3:17]
Reactant: CC(C)Cc1ccc(O)cc1O
Reactant: CCOCC
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(CC(C)C)c(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Isobutyl-benzene-1,3-diol (1 eq) was taken up in BF3.OEt2 (6 eq) and acetic acid (2 eq) was added. The solution was heated for 16 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted twice with diethyl ether. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-5-isobutyl-phenyl)-ethanone, which was used without additional purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]1[OH:16].[CH:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[C@@H:4]([OH:16])[C@H:3]([NH:2][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:11]2
Reactant: COc1cc2c(cc1OC)C(O)C(N)C2
Reactant: CCCCCCCC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCCCN[C@@H]1Cc2cc(OC)c(OC)cc2[C@H]1O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.5 g of 2-amino-5,6-dimethoxy-1-indanol hydrochloride (10.2 mmole) (R. Perrone et al., il Farmaco, Ed. Sci., 39, 255-264, 1984), 1.44 g of octanal (11.2 mmole) and 100 ml of methanol, 2.5 g of sodium cyanoborohydride (39.8 mmole) is added gradually with stirring at 5° C. The mixture is then allowed to stand at room temperature overnight with stirring, then the mixture is made acidic by the addition of dilute HCl while cooling at 5° C., then sodium bicarbonate is added to alkaline reaction and the mixture is extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The crude residue is purified by crystallization from acetone/hexane. Yield 1.5 g (45.7%); m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]([CH3:28])[NH2:27])=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]([CH3:28])[NH:27][C:14]([C:10]2[S:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:17][CH3:18])=[N:12][C:11]=2[CH3:13])=[O:16])=[CH:23][CH:22]=1
Reactant: COc1ccc(CN(C)N)cc1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(C)NC(=O)c2sc(-c3ccc(Cl)cc3OC)nc2C)cc1
Yield: 67.6 %

Procedure:
To N,N-dimethylformamide (12 ml), 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (1.02 g) prepared in Example 7-1, N-(4-methoxybenzyl)-N-methylhydrazine (718 mg) prepared in Example 14-1, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (828 mg), 1-hydroxy-1H-benzotriazole monohydrate (662 mg) and N,N-diisopropylethylamine (558 mg), and the mixture was stirred at a room temperature for 22 hours. An ethyl acetate-toluene (3:1) solution was added thereto. The resulting mixture was washed with water, a 5% potassium bisulfate aqueous solution, a saturated sodium bicarbonate solution and a saturated saline solution in order, and then dried over sodium sulfate and concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform:methanol=100:1) to give the title compound (1.05 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(C)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)CC(=O)O)CC2)c(C(C)(C)C)c1
Yield: 95.8 %

Procedure:
To a stirred solution of ethyl 3-[4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl]-3-oxopropanoate (Example 83, 0.210 g, 0.61 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was to evaporated under reduced pressure to provide 3-[4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl]-3-oxopropanoic acid (0.186 g, 96%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Br)[CH:13]=1.BrCC1C=CC=C(F)C=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH2:18][O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2cccc(Br)c2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene according to the procedure from Example 199A substituting 1-bromo-3-bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].BrOBr.[C-:14]#[N:15].[Na+].CO>O>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][C:14]#[N:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: C[C@H](CBr)COC(C)(C)C
Agent: BrOBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CC#N)COC(C)(C)C
Yield: 64.6 %

Procedure:
A mixture of 23.1 g. (0.11 mole) of bromo ether (S)-(+)-3-tert. butoxy-2-methyl-1-bromopropane and 11.07 g. (0.225 mole) of sodium cyanide in 144 ml. of methanol and 36 ml. of water was stirred and refluxed for 17 hours. After cooling, the reaction mixture was diluted with water and worked up by extraction with CH2Cl2 in the manner of Example 1. The crude product was chromatographed on 500 g. of silica gel. Elution with 9:1 parts by volume and 4:1 parts by volume hexane-ether followed by evaporative distillation gave (R)-(+)-4-tert. butoxy-3-methylbutyronitrile (11.03 g.; 64.5%) as a colorless liquid, b.p. 88°-90° C. (bath temperature) (11 mm Hg.); [α]25D+7.41° (c 1.8, C6H6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH:8]([CH2:10][OH:11])[O:9][C:5]=2[CH:4]=1.CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH:8]([CH2:10][O:11][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)OC(CO)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of (RS)-(6-methoxy-2,3-dihydro-benzofuran-2-yl)-methanol (0.09 g, 0.5 mmol), Et3N (0.1 ml, 0.75 mmol), DMAP (1 mg, 0.01 mmol) in CH2Cl2 (1.5 ml) at 0° C. was added dropwise a solution of p—toluenesulfonylchloride (115 mg, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and was stirred during 4 hr before the addition of H2O (2 ml). The aqueous phase was extracted with CH2Cl2 (2×5 ml). Combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with nHexane-EtOAc (4:1) to provide (RS)-toluene-4-sulfonic acid 6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (120 mg, 72%) as a colorless oil, MS:m/e=334 (M+).