Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][N:15]=1>CN(C=O)C>[N:21]1([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[N:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCCCN1CCCCC1
Reactant: Brc1ccc(CN2CCCCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCCCN2CCCCC2)ncc1CN1CCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (1.5 mmol) in DMF is added 3-piperidin-1-yl-propan-1-ol (1.1 mmol). After 30 min, 2-bromo-5-piperidin-1-ylmethyl-pyridine (1 mmol) is added to the mixture. After 18 h, the reaction is extracted with ethyl acetate (100 mL) and washed with 1 N NaHCO3 (50 mL) and H2O(3×50 mL). The organic layer is dried, concentrated, and chromatographed on SiO2 to provide the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[Cl-].[CH3:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH2:45][C@H:46]2[CH2:50][CH2:49][C@@H:48]([NH2:51])[CH2:47]2)[CH2:40]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:51][C@@H:48]4[CH2:49][CH2:50][C@H:46]([CH2:45][N:41]5[CH2:42][CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40]5)[CH2:47]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1CCCN(C[C@H]2CC[C@@H](N)C2)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in 50 ml DCM, Oxallyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) then kept under N2 atmosphere. (1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentanamine (Intermediate 10, 0.21 g) in DCM, triethyl amine (0.3 ml, 3.12 mmol) was added at 0° C. and stirred for about 15 minutes followed by above prepared acid chloride was added and stirred at room temperature for about 8 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); 6.12-6.15 (m, 1H); MASS: 763 (100%).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]([CH:12]=[O:13])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[C:6]([CH:12]([OH:13])[CH3:1])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=Cc1nc(Cl)ccc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
Methyl magnesium bromide (3.0M Et2O, 0.25 mL, 0.75 mmol) was added dropwise to a THF (2 mL) solution of 3,6-dichloropyridine-2-carbaldehyde (100 mg, 0.57 mmol) cooled to 0° C. After 1 hour the solution was partitioned between ethyl acetate and 1N aqueous HCl. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J=8.4 Hz, 1H); 7.30 (d, J=8.2 Hz, 1H); 5.22-5.14 (m, 1H); 3.83 (d, J=8.7 Hz, 1H) 1.50 (d, J=6.5 Hz, 3H). LCMS1 2.40 min. (M−H2O)=174
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[BH4-].[Na+]>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CC(O)CC(C)(C)N1

Procedure:
2,2,6,6-tetramethyl-4-piperidinol was prepared by the reduction of 2,2,6,6-tetramethyl-4-piperidone (Aldrich) with sodium borohydride. It was purified by recrystallization from ligroin (bp 65-90). It formed colorless needles with mp 130-131; the reported mp is 128-131 (Lutz et al 1962).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[O:25][C:24](=O)[C:23]=2[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[CH:18][CH:17]=1)(=O)C.Cl>O.C(OCC)(=O)C>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[O:25][CH2:24][C:23]=2[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(-c3ccc(OC(C)=O)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)OCC(c1ccc(C(F)(F)F)cc1)=C2c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (200 ml) solution of 4-(4-acetoxyphenyl)-7-methoxy-3-(4-(trifluoromethyl)phenyl)-coumarin (4.54 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric acid (30 ml). The resulting mixture was heated to 60-65° C. for 3 h, cooled and diluted with water (100 ml) and ethyl acetate (50 ml). The aqueous layer was separated and further extracted with ethyl acetate (3×100 ml). The combined organic solutions were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an orange solid. This was recrystallised from ethanol/water (65 ml, 10:3) to give the first crop of solid product as colourless needles. The mother liquors were evaporated to give an orange gum, which was subjected to a second aqueous ethanol recrystallisation to give a second crop of colourless needles. The solids were combined and vacuum dried.
Reaction SMILES: [C:1]1(=[N:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[N:10]O)[CH2:2]1.[Na].O>C(O)C>[NH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([NH2:12])[CH2:2]1
Reactant: ON=C1CC(=NO)c2ccccc21
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC1CC(N)c2ccccc21
Yield: 69.5 %

Procedure:
To a solution of 20 g of a 1,3-indandione dioxime in 2 L of absolute ethanol was cautiously added 160 g of sodium in portions during 1 hr (at such a rate to maintain reflux). After disappearance of the sodium, 300 mL of water was slowly added and the solution concentrated in vacuo to remove most of the ethanol. The resulting solution was acidified with conc. hydrochloric acid to pH 1-2 followed by extraction with methylene chloride to recover unreacted started material. The aqueous layer was basified with 10% sodium hydroxide to pH 12 and extracted with methylene chloride which gave 11.7 grams of crude 1,3-diaminoindan upon solvent removal in vacuo. Purification of this material by flash column chromatography eluting with 95% ethanol/ammonium hydroxide (400:16) gave 8.75 g of the title compound as an approximately 60/40 mixture of cis to trans isomers.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18].C(OC(C)C)(C)C>[Zn]>[C:17]([O:21][C:3](=[O:2])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CNC(=O)OCc1ccccc1
Yield: 91.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 91.8%.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>>[CH2:34]([O:35][CH2:36][CH2:37][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:29])[CH2:14][CH2:15]2)=[CH:20]1)[CH3:33]
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3c(C)cccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2cccc(C)c21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.068 g (0.172 mmol) of 2-{2-[4-(7-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 138, part A), 0.010 g (0.26 mmol) of NaH in 60% of mineral oil and 0.023 mL (0.22 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.074 g (93% of yield) of the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)=[O:16])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(O)(=O)=O>[CH2:1]([N:8]1[C:12]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:21]=3)[C:15](=[O:16])[CH2:14]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cc1ccc(C(=O)C=Cc2cncn2Cc2ccccc2)cc1
Agent: CS(=O)(=O)O
Product: CC(C)Cc1ccc2c(c1)C(c1cncn1Cc1ccccc1)CC2=O
Temperature: 120 °C

Procedure:
A mixture of 3-(3-benzyl-3H-imidazol-4-yl)-1-(4-isobutylphenyl)-propen-1-one (2.4 g) and methanesulfonic acid (40 ml) is heated at 120° C. for 40 minutes. Work-up of the reaction mixture gives the crude product, which is purified by flash chromatography by eluting with methylene chloride-methanol solution. The yield is 0.5 g.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21](I)[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(I)c(N)nc1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(C#C[Si](C)(C)C)c(N)nc1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5'-deoxy-2',3'-di-O-acetyl-5-iodocytidine (1.35 g, 3.087 mmol) in CH2Cl2 (15 ml) there was added N,N-diisopropylethylamine (0.537 ml, 3.087 mmol), Cul (58 mg, 0.309 mmol), Pd(PPh3)2Cl2 (60 mg, 0.085 mmol), and trimethylsilyl-acetylene (0.523 ml, 3.704 mmol) at room temperature under Ar. The reaction mixture was then heated to 60° C. After stirring for 2 hours, the mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue dissolved in EtOAc (200 ml), washed with 2% aq. EDTA.2Na, water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (f2.2×25 cm, eluent: EtOAc) to give 2',3'-di-O-acetyl-5'-deoxy-5-[2-(trimethylsilyl)ethynyl]cytidine as a pale yellow solid. (1.20 g, 95% y.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH2:31][CH2:32][CH3:33]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:28][N:29]=[C:30]([CH2:31][CH2:32][CH3:33])[N:27]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH2:11]1>>[CH:6]1[C:3]2[C@H:4]3[C@H:16]([CH2:15][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:19]=4[O:5]3)[CH2:17][CH2:18][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1O
Reactant: C1=Cc2ccccc2CC1
Product: c1ccc2c(c1)C[C@@H]1CCc3ccccc3[C@@H]1O2
Yield: 6.9 %

Procedure:
2-Hydroxybenzyl alcohol (5.0 g) and 1,2-dihydronaphthalene (5.2 g.) were heated together at 190° for 2 hr. the reaction mixture was chromatographed on neutral alumina, eluting with toluene/60°-80° petroleum ether 1:1to give a solid product which was recrystallised from ethanol to yield colourless crystals of cis-5,6,6a,12a-tetrahydro-7H-benzo(c)xanthene(0.65 g., m.pt. 71°-72°)identified and characterised by 1H- and 13C n.m.r. spectra.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:30][S:31](=[O:35])(SC)=[O:32].[OH-].[Na+].ClC1C=C(C=CC=1)C(OO)=O.S(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([S:31]([CH3:30])(=[O:35])=[O:32])=[CH:3][CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)cc2)=NO1
Reactant: CSS(C)(=O)=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of 3-(4-bromophenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product of Step A) (4.39 mg, 1.00 mmol) in tetrahydrofuran (10 mL) cooled below −75° C. was added a solution of n-butyllithium (2.5 M solution in hexanes) dropwise over three minutes, while maintaining the temperature at or below −72° C. Within one minute, S-methyl methanesulfonothioate (0.11=L, 1.2 mmol) was added dropwise. The reaction mixture was allowed to stir and warm slowly to ambient temperature, and then it was poured into 1 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate; and concentrated. The residue was subjected to chromatography on silica gel eluted with 10% ethyl acetate in hexanes. The isolated material was redissolved in dichloromethane (5 mL), treated with 3-chloroperoxybenzoic acid (˜77%, 0.39 g, 1.7 mmol) and allowed to stir at ambient temperature for 64 h. Additional 3-chloroperoxybenzoic acid (˜77%, 0.27 g, 1.2 mmol) was added, and the mixture was stirred for 4 h. To this mixture was added saturated aqueous sodium bisulfite solution, and then solid potassium carbonate was added carefully until gas evolution ceased. The phases were separated, and the organic phase was washed with 1 N aqueous sodium hydroxide solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and hexanes to obtain a solid which was collected on a glass frit. The solid was washed with a mixture of diether and hexanes, and dried to afford the title product (0.12 g), a compound of the present invention.
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH2:27])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH:27][C:37]([CH2:36][NH:35][C:33](=[O:34])[C:32]5[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:44])([F:28])[F:43])[CH:31]=5)=[O:38])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step, 550 mg, 1.10 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 272 mg, 1.10 mmol) in DCM (10 mL) was treated with TEA (770 μL, 5.5 mmol) at room temperature. The mixture was treated with EDCI (Aldrich, 252 mg, 1.32 mmol), HOBT (Aldrich 149 mg, 1.10 mmol), and the reaction was stirred at room temperature for additional 6 hours. The reaction was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([PH:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6].[CH3:12]I.O>O1CCCC1.ClCCl>[CH2:3]([P:7]([CH3:12])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCC[PH](=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCP(C)(=O)OCC

Procedure:
A suspension of 8.0 g of sodium hydride (55% dispersion in oil) in 35 ml of anhydrous tetrahydrofuran under an inert atmosphere is treated with 35 ml of an anhydrous tetrahydrofuran solution of 25 g of ethyl n-butylphosphinate. The resulting suspension is stirred at room temperature for 1 hour before dropwise addition of 32 ml of methyl iodide. After 3 hours stirring at room temperature 10 ml of water are carefully added followed by 200 ml of dichloromethane. Separation of the organic layer, drying over anhydrous magnesium sulphate and removal of the solvent in vacuo affords an oil. Kugelrohrdistillation at 90° and 10-1 mbar affords ethyl n-butyl-(methyl)phosphinate.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:26][C:27]1[C:28]([NH2:33])=[N:29][NH:30][C:31]=1[NH2:32].Cl>CO>[NH2:32][C:31]1[C:27]([CH2:26][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:24])([F:23])[F:25])[C:16]=2[CH3:15])=[C:28]2[N:33]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:29]2[N:30]=1
Reactant: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Agent: Cl
Solvent: CO
Product: Cc1c(Cc2c(N)nn3c(O)cc(C4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 65 °C

Procedure:
To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.2 g, 0.999 mmol) and 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (0.270 g, 0.999 mmol) was added Methanol (4 mL) and hydrochloric acid (0.4 mL, 0.500 mmol) in methanol (1.25 N). The reaction vessel was sealed and heated at 65° C. for 6 days. The reaction mixture was concentrated to 1 mL. The solid was filtered and wash with methanol (2 ml×3) and dried (0.19 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.84 (m, 4H) 2.47 (s, 3H) 2.58-2.75 (m, 1H) 3.34-3.39 (m, 2H) 3.85 (s, 2H) 3.93 (dd, J=11.24, 3.16 Hz, 2H) 5.28 (s, 2H) 5.41 (d, J=1.52 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.28 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.18 (s, 1H); LC/MS: MS (ES+) m/e 407.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[N:56]1([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCOCC1>[CH3:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[N:59]1[CH2:58][CH2:57][N:56]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:61][CH2:60]1
Reactant: COc1cc(Br)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 37.6 %

Procedure:
to a stirred solution of 1-bromo-2-methyl-5-(methyloxy)-4-nitrobenzene (9 g, 36.6 mmol) in 180 mL of Dioxane was added Pd2(dba)2 (2.14 g, 2.34 mmol), XANTPHOS (2.12 g, 3.65 mmol), cesuim carbonte (50 g, 153.6 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (13.6 g, 73.15 mmol). The resulting slurry was warmed to 60° C. for 24 hours. The dioxane was removed under reduced pressure and the crude mixture was taken up in ether and filtered to remove cesium carbonate. The ether was, washed with water, dried (Na2SO4), filtered, and rotovaped down. The crude product was purified by flash chromatography to give 1,1-dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (4.83 g, 13.75 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (s, 1 H), 6.56 (s, 1 H), 3.92 (s, 3 H), 3.52-3.63 (m, 4 H), 2.88-2.99 (m, 4 H), 2.25 (s, 3 H), 1.47 (s, 9 H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21](I)=[C:20]([CH3:26])[CH:19]=2)[CH2:15][CH3:16])=[CH:12][CH:13]=1)=[O:8].[C:28]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[C:22]([CH3:24])=[CH:23][C:18]([O:17][CH:14]([C:11]3[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:8])=[CH:13][CH:12]=3)[CH2:15][CH3:16])=[CH:19][C:20]=2[CH3:26])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCC(Oc1cc(C)c(I)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Product: CCC(Oc1cc(C)c(-c2ccc(C(C)(C)C)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)s1

Procedure:
This compound is made by the general method as exemplified in Example 44 using 3-({5-[1-(4-iodo-3,5-dimethyl-phenoxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (isomer 1) and (4-tert-butyl)phenylboronic acid as the starting materials. MS (ES): 494.4 [M+H]+.