Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:10][CH:9]=[N:8][N:7]2[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1.O[C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:6]3[N:7]([C:18]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)=[C:4]([CH2:3][CH2:2][O:1][C:39]4[CH:40]=[N:41][C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:5]=3)[N:8]=[CH:9][CH:10]=2)[CH2:13][CH2:14]1
Reactant: Oc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCOc4cnc5ccccc5c4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 28f (97.3 mg, 0.191 mmol), 3-hydroxyquinoline (38.8 mg, 0.267 mmol), and PPh3 (70.1 mg, 0.267 mmol) were placed in an 8 mL vial equipped with a stir bar. DCM (2 mL) was added and the mixture was stirred at rt for 5 min. 40% Diethyl azodicarboxylate in toluene (0.104 mL, 0.229 mmol) was added dropwise and then the resulting solution was stirred at rt for 30 min. The crude reaction was chromatographed on a 12 g SiO2 pre-packed column and eluted with 0-80% ACN/DCM to afford compound 28g. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.59 (d, J=2.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.95-8.05 (m, 2H), 7.84 (dd, J=8.8, 2.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.45-7.59 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.51 (t, J=6.7 Hz, 2H), 3.87-4.00 (m, 8H), 3.52-3.65 (m, 8H), 3.38 (t, J=6.7 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H40N8O4: 637.3 (M+H). Found: 637.3.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20]Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20][N:32]1[CH2:33][CH2:34][N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][CH2:31]1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCN1CCN(c2ccccc2)CC1
Yield: 70.7 %

Procedure:
A mixture of 3.46 g of N-(2,6-diisopropylphenyl)-2(2-chloroethylsulfonyl)acetamide synthesized in (1) above, 1.62 g of N-phenylpiperazine, and 50 ml of toluene was heated under reflux for 4 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with a sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a mixture of ethyl acetate and hexane at a ratio varying from 1:1 to 1:0 as a developing solvent. The solvent was evaporated, and the residue was dissolved in ethyl acetate and crystallized from a 4N hydrochloric acid solution in ethyl acetate to obtain 3.33 g of the title compound as white powder (m.p.=197.0°-200.0° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:22]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].CO>C(O)=O>[ClH:2].[NH2:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[Cl:2])[N:10]=[CH:9][N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=1
Reactant: C#Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(Cl)c(N)cc23)c1
Reaction time: 16 h

Procedure:
(7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (166 mg, 0.295 mmol) and sodium dithionite (207 mg, 1.19 mmol) were stirred in 1.5 mL of formic acid for 4 hours at room temperature. 45 mL of methanol were added to the reaction mixture which was set aside for 16 hours at room temperature. The precipitate thus obtained was filtered, triturated with 3% sodium bicarbonate for 0.5 hours and refiltered. The solid was dissolved in 20 mL of 1N HCl in methanol and precipitated with 200 mL of ethyl ether. This was filtered and dried in vacuo at 70° C. to afford the title product, 72 mg (83%); mp 260°-265° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCOc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Piperidine (158 mL, 1.59 mol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (302 g, 1.59 mol) and 2-[(carboxyacetyl)amino]benzoic acid (322 g, 1.44 mol) in toluene (1.5 L). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 L) and water (1 L) at 50° C. and the solution was acidified with 50% aqueous AcOH. The precipitate was filtered and the crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (309 g, 61%) as a yellow crystalline solid; mp 201-203° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, C≡CH), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5,6=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C20H17NO5 [M+H]+ 352.1179, found 352.1187; νmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (19 μL, 0.18 mmol) was added to a solution of triethylamine (25 μL, 0.18 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (70 mg, 0.164 mmol). The reaction mixture was stirred at room temperature for 2 h. It was diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were removed under reduced pressure and chromatography of the residue over silica gel using 0.5-1% methanol in methylene chloride gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazole-1-yl]-2-methyl-propan-1-one. HR-MS (EI, m/z) calculated for C27H26N2O3Cl2 (M+) 496.1320, observed 496.1319.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][NH:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]([S:42](Cl)(=[O:44])=[O:43])[CH:34]=[CH:35][C:36]=1[O:37][C:38]([F:41])([F:40])[F:39]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][N:13]2[S:42]([C:33]2[CH:34]=[CH:35][C:36]([O:37][C:38]([F:39])([F:40])[F:41])=[C:31]([I:30])[CH:32]=2)(=[O:44])=[O:43])=[O:11])=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(I)c1
Reactant: CC(=O)N1CCN[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)c(I)c2)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 3 and triethylamine (66 μl) in chloroform (0.4 ml) was added, with stirring at room temperature, 3-iodo-4-trifluoromethoxybenzenesulfonyl chloride (68 mg). After stirring at room temperature for 1 hr, the reaction mixture was directly purified by thin layer chromatography (methanol:chloroform=1:15) and recrystallized from water-containing methanol to give the title compound (53 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:30]=1)[CH3:36]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int c) and ethyl 3-hydroxybenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (32%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][CH2:11][NH:12][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N#CCC(O)c1ccc(F)c(Br)c1
Agent: B
Solvent: C1CCOC1
Product: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F

Procedure:
Reduction of 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile with BH3-THF following the method used in Example 17, followed by protection of the amine with ethyl trifluoroacetate following the method used in Example 9 gave N-(3-(3-bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a clear oil. Yield (4.3 g, 73%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (bs, 1H), 7.62 (dd, J=6.8, 2.0 Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (t, J=8.8 Hz, 1H), 5.48 (d, J=4.4 Hz, 1H), 4.60-4.56 (m, 1H), 3.28-3.15 (m, 2H), 1.84-1.71 (m, 2H).
Reaction SMILES: C[O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=O.O.[NH2:25][NH2:26]>CO>[C@@H:9]1([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH:5]([C:3]([NH:25][NH2:26])=[O:2])[OH:23])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: NN
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CO
Solvent: O
Product: NNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 93 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are suspended in 150 ml of methanol mixed with 20 ml of hydrazine hydrate and heated to the boil. The ester thereby goes into solution, while, almost simultaneously, the hydrazide precipitates out in the form of a fine crystalline material. After standing overnight, it is filtered off with suction, washed with methanol and dried. There are obtained 4.4 g of adenosine-5'-carboxylic acid hydrazide, which melts, with decomposition, at 270°-272° C. The yield is 93% of theory. The compound can be readily recrystallized from hot water.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.[CH3:23][C:24]1[C:25]([NH2:39])=[N:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[O:31][CH2:30][CH2:29]2)[N:28]=1.Cl>C(Cl)Cl.CN(C=O)C>[NH2:39][C:25]1[C:24]([CH3:23])=[N:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:20](=[O:22])[C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=4)[CH:36]=3)[O:31][CH2:30][CH2:29]2)[N:26]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)N=C1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) was added to a suspension of 5-chloropyridine-2-carboxylic acid (37 mg, 0.23 mmol) in DCM (1.5 mL). The obtained solution was stirred for 10 min and added dropwise over 2 min to an ice-cooled solution of 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol) and 2 M HCl (0.117 mL, 0.23 mmol) in DMF (1.5 mL). The mixture was stirred at 0° C. for 5 min. Volatiles were removed in vacuo, and the residue was purified by preparative chromatography. Fractions containing the product were combined, and the organic solvent was removed in vacuo. The aqueous residue was alkalized with (sat) NaHCO3 and then extracted twice with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to give a product which was purified by flash chromatography (4 g, gradient elution (EtOAc/MeOH/conc. NH3) in heptane) affording the title compound (27 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (br. s., 2H), 2.23 (s, 3H), 4.23-4.54 (m, 2H), 6.56 (br. s., 2H), 6.80 (d, 1H), 7.05 (br. s., 1H), 7.54-7.72 (m, 1H), 8.04-8.12 (m, 1H), 8.13-8.23 (m, 1H), 8.72 (br. s., 1H), 10.41 (s, 1H); HPLC, MS (APCI+) m/z 370 [M+H]+.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.C([Li])CCC.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][O:47][C:48]2[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=2)[CH2:41][CH2:40]1>O1CCCC1.CCCCCC>[CH3:33][C:3]1([CH3:2])[S:7][C:6]2[CH:8]=[CH:9][C:10](/[C:12](/[CH3:13])=[CH:52]/[C:51]3[CH:50]=[CH:49][C:48]([O:47][CH2:46][CH2:45][N:42]4[CH2:41][CH2:40][O:39][CH2:44][CH2:43]4)=[CH:55][CH:54]=3)=[CH:11][C:5]=2[S:4]1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C(=C\c1ccc(OCCN2CCOCC2)cc1)c1ccc2c(c1)SC(C)(C)S2
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 35.2 %

Procedure:
6.6 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were dissolved in 40 ml of tetrahydrofuran and treated slowly at 0° C. with 9 ml of a 1.5 molar solution of n-butyllithium in hexane. After 40 minutes, 3.5 g of 4-(2-morpholinoethoxy)benzaldehyde in 10 ml of tetrahydrofuran were added dropwise to the dark red solution and the mixture was stirred at 20° C. for 16 hours. The mixture was then poured on to ice and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated. After chromatography (silica gel, eluting agent ethyl acetate) and crystallization from ether/hexane, there were obtained 1.8 g of 4-[2-[p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenoxy]ethyl]morpholine in the form of colorless crystals, melting point 90°-91° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:8]([OH:11])(=[O:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N-:22][CH:23](C)C)=[CH:18][C:17]=1[CH2:26][NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:23])[S:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])(=[O:10])=[O:11])=[CH:18][C:17]=1[CH2:26][NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:14])[CH3:13]
Reactant: CC(C)[N-]c1ccc(OC(C)C)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Reactant: Cc1nc(C)c(S(=O)(=O)O)s1
Product: Cc1nc(C)c(S(=O)(=O)N(C)c2ccc(OC(C)C)c(CN[C@H]3CCCN[C@H]3c3ccccc3)c2)s1

Procedure:
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl-isopropylamide;
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1CCC[C@H](N)C1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CCC[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Acetic anhydride (1.20 ml, 12.7 mmol) was added to a solution of trans-methyl 3-aminocyclohexane-carboxylate (0.40 g, 2.54 mmol) in pyridine (10 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The volatiles were removed in vacuum, the resulting residue was dissolved in DCM and washed with saturated sodium bicarbonate solution followed by brine solution (10 ml). After drying over anhydrous sodium sulfate and filtration the filtrate was concentrated under vacuum to afford 350 mg (69.0%) of trans-methyl 3-acetamidocyclohexanecarboxylate as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][N:4]=1>C(O)C.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][N:4]=1
Reactant: CCOC(=O)C=Cc1cnc(OC)nc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCc1cnc(OC)nc1

Procedure:
A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10% palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. The catalyst was filtered off through hyflo and the filtrate evaporated. The residue was dissolved in dichloromethane, washed twice with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated to an oil, yield 41.2 g (78%). 1H-NMR (CDCl3) δ1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H)=211; C10H14N2O3 requires 210.
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][CH:7]([C:17]1[C:18]([CH3:41])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([Si:5]([CH3:42])([CH3:43])[O:6][CH:7]([C:17]1[C:18]([CH3:41])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3([CH2:37][C:38]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:39])[CH2:35][CH2:36]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the procedure described in Example 315 using [1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropyl]-acetic acid and methanesulfonamide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>CCOCC>[F:27][C:26]([F:29])([F:28])[S:23]([O:11][C:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]=1)(=[O:24])=[O:22]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: -15 °C
Yield: 65 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (1.0 equiv) was dissolved in Ether (0.1M) and stirred at −15° C. then 1M NaHMDS (1.05 equiv.) was added and stirred for 70 min then Tf2O (1.05 equiv.) added and reaction allowed to slowly warm to rt. The mixture was stirred for 28 hr, washed with sat. aq. NaHCO3 and then water. Aqueous layers combined and extracted with ether. Organic layers combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl ether:hexanes=1:4) to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (65%). LC/MS (m/z): MH+=289.0, Rt=0.97. HPLC Rt=3.77.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CC1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CC1CCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and 2-methyl-pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, d4-methanol) δ 7.83 (m, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.57 (m, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 3.2-3.9 (m, 7H), 2.35 (m, 1H), 2.10 (m, 2H), 1.76 (m, 1H), 1.48 (d, J=7.2 Hz, 3H); MS (DCI) m/z 419 (M+H)+;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)[NH:14]S(C(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(Cl)[Cl:27].Cl>CCOCC>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)[NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: ClCCl
Reactant: CC(C)(C)S(=O)NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Agent: Cl
Solvent: CCOCC
Product: NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of 55 (570 g, 1.5 mol) and DCM (10 mL) was added HCl (3.74 mL, 1.5 mol) and the solution stirred for 30 min. The reaction mixture was added dropwise to a stirred solution of ether. The solids were filtered and washed with Et2O to afford 223 mg (47.6%) of (3-fluoro-4-(trifluoromethoxy)phenyl)(oxazol-5-yl)methanamine hydrochloride (56).