Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:23][C:11]2[N:12]=[C:13]([NH2:22])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=1)=[O:7])C>C(O)C.O>[NH2:22][C:13]1[N:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:23][C:11]=2[N:12]=1
Reactant: CCOC(=O)c1cc2c(-c3ccccc3)nc(N)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccccc2)c2cc(C(=O)O)sc2n1
Temperature: 25 °C

Procedure:
Sodium Hydroxide (0.66 g; 16.5 mmol) was added to a suspension of 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 1) (1.00 g; 3.34 mmol) in ethanol (20 ml) and water (2 ml). The mixture was heated at reflux for 1 hour (affording a homogeneous pale-yellow solution) and allowed to cool to ambient temperature. Solvents were removed in vacuo and the solid residue was dissolved in water (30 mL) and cooled with ice-water bath. The mixture was stirred and adjusted to pH 1-2 by drop-wise addition of concentrated Hydrochloric acid. The resulting precipitate was filtered, washed with water, then ethanol and finally diethyl ether. The off-white product was dried in vacuo to afford 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid as a colourless solid (0.784 g; 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].CC(=CC)C.C([OH:18])(C)(C)C.[O-]Cl=O.[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:18])=[O:8]
Reactant: CC(C)(C)O
Reactant: O=Cc1scnc1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1scnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirring mixture of 10.3 g (69.8 mmol) 4-chloro-thiazole-5-carbaldehyde (Journal of the Chemical Society, Perkins Transactions, 1992, 973-978), 296 ml (2792 mmol) 2-methyl-2-butene, and 200 mL tertiary butanol was added a solution of 50.5 g (558 mmol) NaClO2, 50.2 g (419 mmol) NaH2PO4 in 300 mL of water, dropwise over 20 minutes. The reaction was stirred for 1 hour then concentrated to ⅓ volume via rotary evaporation. The remaining solution was acidified with 6N HCl with rapid stirring. The precipitated solid was filtered and air dried under high vacuum overnight to give 10.6 g of white solid.
Reaction SMILES: C([C:3]1[C:4](CC)=[C:5]([C:14]([CH3:21])([C:18]([O-:20])=[O:19])C([O-])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])C.[OH-].[K+].[CH3:26][CH2:27]O>>[C:11]([CH2:10][CH2:9][C:8]1[CH:3]=[CH:4][C:5]([CH:14]([CH3:21])[C:18]([O:20][CH2:26][CH3:27])=[O:19])=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CCO
Reactant: CCc1c(CCC(=O)O)ccc(C(C)(C(=O)[O-])C(=O)[O-])c1CC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(C)c1ccc(CCC(=O)O)cc1

Procedure:
The tricarboxylic ester of Example 6 (35 g, 0.1 mol) in EtOH (400 ml) was stirred at room temperature with a solution of KOH (13.2 g of 85%, 0.2 mol) in EtOH (100 ml) for 96 hours. The mixture was evaporated to dryness. The solid foam was broken up, treated with Et2O (200 ml) and filtered. The residue was dissolved in H2O (100 ml), acidified with 5 N HCl to give an oil which was extracted with Et2O. The Et2O was dried (Na2SO4) filtered and evaporated to give an oily solid. The solid was shaken with a mixture of CHCl3 -light petroleum (b.p. 40°-60° C.) (100 ml of 50:50), filtered, the residue washed with the same solvent mixture (100 ml) and the filtrate evaporated to leave an oil which was distilled to give the title product, b.p. 175°-7° C./0.25 mm.
Reaction SMILES: N1[C:5](=O)[CH2:4][CH2:3][C@H:2]1[C:7](O)=O.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[Br-:20].[Li+]>C(O)C.CC(C)=O.C(N(CC)CC)C>[Br:20][CH2:7][C:2]#[C:3][CH2:4][CH2:5][CH2:7][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCC#CCBr

Procedure:
Pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether can be prepared by coupling propargyl alcohol tetrahydropyranyl ether with n-hexyl bromide in the presence of lithium amide, to produce 2-nonyn-1-ol tetrahydropyranyl ether, then hydrolysing of the tetrahydropyranyloxy function with Pyr/PTS in ethanol solution followed by esterification of the hydroxy compound with methanesulfonyl chloride in the presence of triethylamine. The mesylate is then reacted with lithium bromide in acetone solution to produce 1-bromo-2-nonyne. Finally the latter compound is coupled with hexa-2,5-diyn-1-ol-tetrahydropyranyl ether in the presence of ethylmagnesium bromide and cuprous chloride. The sequence of reaction conditions are essentially the same as those described hereinafter in detail.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH3:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][O:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:34]2[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29][O:28][CH2:27][C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:38][CH:37]=3)[CH2:36][CH2:35]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: Cc1ccc(COCCC2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(COCCC2CCN(c3cncc(OC[C@@H]4CCCN4C(=O)OC(C)(C)C)c3)CC2)cc1
Temperature: 99 °C
Yield: 63.8 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (254 mg, 0.71 mmol) and 4-[2-(4-methylbenzyloxy)ethyl]piperidine (182 mg, 0.78 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (102 mg, 1.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.0 mg, 14 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 24.7 mg, 43 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. The product (231 mg, 64%) was obtained as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 1,4-diiodobenzene (24.7 g), propargyl alcohol (1.68 g), BTPC (0.21 g) and CuI (28 mg) in diethylamine (180 ml) was stirred at room temperature under nitrogen for 18 h. The solvent was evaporated in vacuo at 35°, the residual solid taken up in MC (200 ml) and the solution washed with 2N hydrochloric acid (150 ml). The aqueous phase was extracted with further MC (75 ml), the organic layers combined, dried and purified by FCC eluting with EA-CX (1:6) and then EA-CX (1:3) to yield the title compound as fawn crystalline solid (4.9 g) m.p. 101°-102°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:38][CH:39]([F:41])[F:40])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([CH:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)C1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)C1Cc2ccccc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 67.9 %

Procedure:
Using the compound (954 mg, 2.27 mmol) of step A and 2,2-difluoroethyl trifluoromethanesulfonate (607 mg, 3.12 mmol), and according to the method of Example 241, step C, the title compound (747 mg, yield 68%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH3:8]>O1CCCC1.C(N(CC)CC)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.[Cu]I>[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:17]=1)[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCC(CC)COc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 64.5 h
Yield: 0.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol) was added to a degassed suspension of trimethylsilyl acetylene (3.00 mL, 2.09 g, 21.2 mmol), 4-(2-ethylhexyloxy)iodobenzene (2) (4.27 g, 12.9 mmol) and copper (I) iodide (294 mg, 1.54 mmol) in tetrahydrofuran (20 mL) and triethylamine (30 mL). The mixture was stirred under argon at room temperature for 64.5 h. The solution was filtered through a short plug of silica with dichloromethane as eluent and the solvent removed. The residue was purified by column chromatography over silica with light petroleum as eluent to leave [4-(2-ethylhexyloxy)phenylethynyl]trimethylsilane (3) (2.93 mg, 75%) as a clear, colourless oil. (Found: C, 75.35; H, 9.85. C19H30OSi requires C, 75.43; H, 10.0%); νmax(film)/cm−1 2156 (C≡C); δH(400 MHz, CDCl3) 0.25 (9 H, s, SiMe3), 0.92 (6 H, m, CH3), 1.30-1.51 (8 H, m, CHCH2CH2CH2CH3 and CHCH2CH3) 1.72 (1 H, m, OCH2CH), 3.84 (2 H, d, J 5, OCH2CH) and 6.82 and 7.40 (4 H, AA′BB′, phenyl H); δc(100.6 MHz, CDCl3) 0.1, 11.1, 14.1, 23.0, 23.8, 29.0, 30.4, 39.3, 70.5, 92.2, 105.3, 114.3, 114.8, 133.4 and 159.6.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[N:10]=[CH:11][CH:12]3[CH:17]([CH:18]=2)[N:16]([CH2:19][CH3:20])[C:15](=[O:21])[C:14]([C:22]2[C:23]([F:41])=[CH:24][C:25]([F:40])=[C:26]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=4)=[O:30])[CH:27]=2)=[CH:13]3)=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:34]1[CH:33]=[C:32]([NH:31][C:29]([NH:28][C:26]2[CH:27]=[C:22]([C:14]3[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH:17]4[CH:12]([CH:13]=3)[CH:11]=[N:10][C:9]([NH:8][CH3:7])=[CH:18]4)[C:23]([F:41])=[CH:24][C:25]=2[F:40])=[O:30])[CH:37]=[C:36]([F:38])[CH:35]=1
Reactant: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(NC)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (0.112 g, 0.185 mmol) and anisole (0.202 mL, 1.849 mmol) in DCM (2 mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3, stirred for 1 h and the resulting solid collected via filtration and dried to afford 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (57 mg, 64% yield). The material was dissolved in MeCN (2 mL), treated with 0.1N HCl (1.17 mL, 0.117 mmol), diluted with water (3 mL), frozen, lyophilized, triturated with Et2O and the resulting solid was collected via filtration and dried to yield 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride (57 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.07 (t, 1H), 7.92 (s, 1H), 7.70 (br s, 1H), 7.40 (t, 1H), 7.15 (d, 2H), 6.82-6.77 (m, 1H), 6.43 (s, 1H), 4.15 (q, 2H), 2.91 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 486.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[CH:7][C:8]=1[CH3:9])#[N:2].S(=O)(=O)(O)[OH:13].[OH-].[Na+]>O>[Cl:11][C:4]1[C:3]([C:1]([NH2:2])=[O:13])=[C:8]([CH3:9])[CH:7]=[C:6]([Cl:10])[N:5]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1C(N)=O
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 3-cyano-2,6-dichloro-4-methylpyridine (270g, 1.44 mole) and concentrated sulfuric acid (530ml) was heated and stirred at 100-110° C. for 3 hours. The resultant mixture was cooled, and poured, with stirring, into 21 of water, to produce a precipitate. The precipitate was neutralized with a sodium hydroxide solution and stirred overnight. The precipitate was then filtered, washed with 31 of water, and dried at 80° C. under vacuum.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCSCC1
Yield: 36 %

Procedure:
N-Cyclopropyl-N-[1-(3-thiomorpholin-4-yl-hexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (41) was prepared as follows. N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and thiomorpholine (2 mL) were heated together at 130° C. for 3 days in a sealed Reacti-vial. The vial was cooled in ice and then the cooled mixture was evaporated to dryness in vacuo in a Speed-Vac®. The residue was chromatographed over flash silica eluting with ethyl acetate:hexane (1:1) to give the title compound 41 (110 mg, 36%) as a white solid. LC: 100%. MS: m/z=548.3, 549.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.15 (1H, s), 8.06 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.73 (1H, d, J=17.7 Hz), 4.10 (1H, m), 3.95 (1H, d, J=17.7 Hz), 3.05 (2H, m), 2.84 (2H, m), 2.74 (2H, m), 2.67-2.43 (6H, m), 2.15 (1H, m), 1.96 (1H, m), 1.75 (3H, m), 1.52-1.22 (4H, m), 0.98 (1H, m), 0.93-0.70 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[CH2:12][C@H:13]4[NH:17][C@@H:16]([C:10]3=[N:9][N:8]=2)[CH2:15][CH2:14]4)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([C:28]([F:31])([F:30])[F:29])=[N:21][CH:22]=[CH:23][C:24]=1[C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[CH2:12][C@H:13]4[N:17]([C:25]([C:24]5[CH:23]=[CH:22][N:21]=[C:20]([C:28]([F:31])([F:29])[F:30])[C:19]=5[Cl:18])=[O:26])[C@@H:16]([C:10]3=[N:9][N:8]=2)[CH2:15][CH2:14]4)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1Cl
Reactant: Clc1ccc(-c2nnc3n2C[C@@H]2CC[C@H]3N2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(c1ccnc(C(F)(F)F)c1Cl)N1[C@H]2CC[C@@H]1c1nnc(-c3ccc(Cl)s3)n1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of (6S,9R)-3-(5-chlorothiophen-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine (Example 55, step b) (35 mg, 0.132 mmol) in DCM (2 mL) was added 3-chloro-2-(trifluoromethyl)-4-pyridinecarboxylic acid (30 mg, 0.132 mmol) followed by HOBt (12 mg, 0.09 mmol), EDCl (38 mg, 0.197 mmol) and TEA (0.04 mL, 0.263 mmol). The reaction was stirred at room temperature overnight and then loaded directly on a SiO2 column eluting with IPA/EtOAc to afford the title compound (53 mg, 85%). MS (ESI): mass calcd. C18H12Cl2F3N5OS, 473.01; m/z found, 473.8 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.75-8.59 (m, 1H), 7.68-7.30 (m, 1H), 7.26-7.13 (m, 1H), 7.03-6.92 (m, 1H), 5.46-5.31 (m, 1H), 4.98-4.87 (m, 1H), 4.65-4.50 (m, 1H), 4.25-3.94 (m, 1H), 2.63-2.23 (m, 3H), 2.00-1.86 (m, 1H).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOCC.CCCCCC>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: Nc1ccc(C#CCCOC2CCCCO2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]aniline were reacted in the presence of LiHMDS solution by the general procedure of Example 1, Step B. After workup, followed by purification by column chromatography on silica gel (50% EtOAc as eluant), unreacted aniline (26%), followed by 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}benzoic acid (31%) were isolated; m.p. (Et2O/hexane) 175–178° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.55 (v br s, 1 H), 9.28 (br s, 1 H), 7.82 (ddd, J=8.2, 6.0, 1.8 Hz, 1 H), 7.25 (dd, J=12.0, 1.7 Hz, 1 H), 7.16–7.08 (m, 2 H), 6.95 (ddd, J=8.8, 8.8, 5.4 Hz, 1 H), 4.66 (t, J=3.4 Hz, 1 H), 3.83–3.70 (m, 2 H), 3.59–3.41 (m, 2H), 2.68 (t, J=6.8 Hz, 1 H), 1.78–1.58 (m, 2 H), 1.53–1.40 (m, 4 H). Anal. calcd. for C22H20F3NO4: C, 63.0; H, 4.8; N, 3.3. Found C, 63.0; H, 4.8; N, 3.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]([O:50]C(/N=N/C(OC(C)C)=O)=O)C.C(O)(=O)C>C1COCC1>[C:48]([O:13][C@@H:11]1[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)(=[O:50])[CH3:47]
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 41, Step E, 260 mg, 0.702 mmol) and PPh3 (460 mg, 1.75 mmol) in THF (10.0 mL) was added DIAD (276 μL, 1.40 mmol) followed by acetic acid (80.4 μL, 1.40 mmol). The reaction was stirred at ambient temperature for 48 hours and then concentrated. The residue was purified by reverse phase column chromatography (0-70% acetonitrile/water) to afford ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (228 mg, 79% yield). MS (apci) m/z=413.0 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: Br[Mg]Cc1ccccc1
Product: OC(Cc1ccccc1)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available benzylmagnesium bromide (available from TCI America) as starting material and making non-critical variations, to yield the title compound. LCMS [M+H]+=374.1 major single peak @ 3.82 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)CCCC.[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:22])/[CH:17]=[CH:18]\[C:19]([O-])=[O:20]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:17]([C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:18][C:19](=[O:20])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: CCCCCOC(=O)/C=C\C(=O)[O-]
Solvent: CCCCCO
Solvent: CC(=O)O
Product: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 75 °C
Yield: 23.8 %

Procedure:
0.75 g of sodium hydroxide was added to a mixed solution comprising 15 ml of 1-pentanol and 30 ml of toluene, followed by dehydration using an azeotropic dehydrator under reflux with heating, and then toluene was distilled off. Further, 20 ml of toluene was added to the reaction system and then toluene was distilled off with heating again, to obtain a 1-pentanol solution of sodium pentaoxide. 2.5 g of 3-chloro-2-hydrazinylpyridine was added to the reaction liquid at from 70 to 80° C. little by little over a period of 5 minutes, and then 5 ml of 1-pentanol was added, followed by heating at from 70 to 80° C. for 25 minutes. Then, a mixed solution comprising 5.1 g of pentyl maleate and 5 ml of 1-pentanol was dropwise added over a period of 15 minutes, followed by reaction at from 70 to 80° C. further for 2 hours. After the reaction liquid was stood to cool, acetic acid was added to the reaction liquid for neutralization, followed by concentration under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid and a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/4 to 0/1) to obtain 1.29 g of the desired product (melting point: 66 to 68° C.) in the form of brown crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2(O)[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:40][CH3:41])[CH:31]=3)[C:26](=[O:42])[N:25]2[CH3:43])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[CH2:8]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[N:25]([CH3:43])[C:26](=[O:42])[C:27]3[C:32]([C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:31][C:30]([O:40][CH3:41])=[CH:29][CH:28]=3)[CH2:22][CH2:23]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)C(O)(C1CCN(C(=O)OCc3ccccc3)CC1)N(C)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(=O)n(C)c(C3CCN(C(=O)OCc4ccccc4)CC3)c(-c3ccccc3)c2c1
Yield: 65.9 %

Procedure:
To trifluoroacetic acid (1 mL) at room temperature was added benzyl-4-(3-hydroxy-6-methoxy-2-methyl-1-oxo-4-phenyl-1,2,3,4-tetra-hydroisoquinolin-3-yl)piperidine-1-carboxylate (215 mg, 0.443 mmol) with stirring. After 10 min. the reaction mixture was made basic with 2N sodium hydroxide, extracted with methylene chloride (3×) and dried with anhydrous sodium sulfate. Filtration followed by evaporation of solvent in vacuo gave a solid which was triturated with hexane-ethyl acetate to afford benzyl-4-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate as a solid (141 mg, 0.292 mmol, 66%). MS [M+H]+ 483.2