Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]([C:6]1[O:7][C:8](Br)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27].C1(NC2CCCCC2)CCCCC1>>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]([C:6]1[O:7][C:8]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(Br)o1
Reactant: C#CCCCCOCCCCCCBr
Agent: C1CCC(NC2CCCCC2)CC1
Product: CCN(CC)C(=O)c1ccc(C#CCCCCOCCCCCCBr)o1
Yield: 73.2 %

Procedure:
N,N-diethyl-5-bromo-2-furancarboxamide (1.5 g) was treated with 6-[(6-bromohexyl)oxy]-1-hexyne (1.59 g) and N,N-dicyclohexylamine (2.10 g) according to the method of Intermediate 9 except that the reaction mixture was refluxed under nitrogen for 3 h and FCC eluting with hexane followed by hexane:ether (4:1→1:1) gave the title compound as an orange oil (1.90 g), t.l.c. (hexane:ether 1:1) Rf 0.15.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Cl:3])=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1ccccc1
Solvent: CCOCC
Product: COc1cc(CCl)ccc1OCc1ccccc1
Yield: 75.4 %

Procedure:
Thionyl chloride (5.95 g, 50.0 mmol) was added to a mixture of 4-benzyloxy-3-methoxybenzylalcohol (10.0 g, 40.9 mmol) in 50 ml ether at room temperature. The reaction turned into a clear solution and was monitored by TLC. The reaction was quenched with H2O. The product was extracted with ether. The aqueous layer was extracted with ether. The combined organic layer washed with 5% NaHCO3, brine and dried with Na2SO4. Ether was evaporated and the residue was purified by chromatography (on silica gel, ethyl acetate/hexane=2/8) to give a white solid 8.10 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([CH3:25])[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:17][CH:18]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(CCl)CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(C2(C#N)CCOCC2)cc1)CN1CCCC1
Yield: 96.2 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (790 mg, 3.87 mmol), 1-(3-chloro-2-methyl-propyl)-pyrrolidine (500 mg, 3.10 mmol), DMF (5 ml) and K2CO3 (2.14 g, 15.50 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. to provide the title compound (979 mg, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.95 (d, 2H), 4.11-4.03 (m, 2H), 4.02 (dd, 1H), 3.89 (td, 2H), 3.77 (dd, 1H), 2.60-2.42 (m, 5H), 2.32 (dd, 1H), 2.22-1.99 (m, 5H), 1.82-1.72 (m, 4H), 1.07 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][NH:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:45])=[N:31][CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Chloro-5-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (1 equiv), 1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (0.1 equiv), sodium carbonate (3 equiv) were suspended in a 3:1 mixture of 1,4-dioxane and water (0.09 M) were combined in a sealed reaction vessel. The resulting solution was flushed with nitrogen and stirred at 85° C. for 2 h. After cooling to room temperature the reaction mixture was loaded directly onto a silica-gel column and purified using flash chromatography (0-55% ethyl acetate in hexane). Fractions were combined, concentrated and the residue dried under high vacuum to give the title compound (61% yield) as a brown semi solid. MS (ESI) m/z 519.1 [M+1]+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]1[C:49]([CH3:50])=[N:48][O:47][N:46]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[C:49]([CH3:50])=[N:48][O:47][N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nonc1Cn1nnc2c(N3CC4(COC4)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as white solid. MS(m/e): 371.3 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])CCC.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1([CH2:27][CH3:28])[CH2:26][O:25][CH2:24]1>C1COCC1>[CH2:27]([C:23]1([CH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:5]2[S:1][C:2]3[CH:8]=[CH:7][S:6][C:3]=3[CH:4]=2)[CH2:24][O:25][CH2:26]1)[CH3:28]
Reactant: c1cc2sccc2s1
Reactant: CCC1(COCCCCCCBr)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2cc3sccc3s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of thieno(3,2-b)thiophene (5.0 g, 35.7 mmol) in anhydrous THF (120 ml) was added n-butyllithium (2.5 M in hexanes, 12.0 ml, 30.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 3-(6-bromohexyloxymethyl)-3-ethyloxetane (8.38 g, 30.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1), to give a yellow oil (7.82 g, 77%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.22 (d, J=5.3 Hz, 1H, Ar—H), 7.14 (d, J=5.3 Hz, 1H, Ar—H), 6.91 (s, 1H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.35 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.41 (t, J=6.4 Hz, 2H, OCH2), 2.84 (t, J=7.4 Hz 2H, ArCH2), 1.35-1.75 (m, 10H, CH2), 0.86 (t, J=7.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 148.3 (quat.), 138.8 (quat.), 137.4 (quat.), 125.4 (CH), 119.5 (CH), 116.3 (CH), 78.6 (OCH2), 73.4 (OCH2), 71.5 (OCH2), 43.4 (quat.), 31.6 (CH2), 31.2 (CH2), 29.5 (CH2), 28.9 (CH2) 26.8 (CH2), 26.0 (CH2), 8.3 (CH3); MS (m/e): 490 (M+, 16%) □305 (79), 223 (25), 205 (100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[CH:39]=[C:27]2[N:28]=[C:29]([NH2:38])[CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]2[N:25]=1.O>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[CH3:23][C:24]1[CH:39]=[C:27]2[N:28]=[C:29]([NH:38][C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:16][CH:15]=3)=[O:14])[CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]2[N:25]=1
Reactant: COC(=O)C1(c2ccc(C(=O)O)cc2)CC1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(C(=O)Nc3cc(-c4ccccc4)n4nc(C)cc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
4-(1-(Methoxycarbonyl)cyclopropyl)benzoic acid (200 mg, 0.91 mmol) was suspended in CH2Cl2 (5 ml). At 0° C., oxalyl chloride (0.50 ml, 1.0 mmol) was then added, followed by 2 drops of DMF. The mixture was warmed to room temperature. After 2 hours, an additional amount of oxalyl chloride (0.15 ml) was added. After the reaction was completed, 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 200 mg, 0.91 mmol) in pyridine (5 ml) was added. After the reaction was complete, water was added and the volatiles were removed in vacuo. The aqueous residue was extracted with EtOAc 3 times. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by preparatory HPLC (65-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow powder (96 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.27 (s, 1 H), 8.08-8.04 (m, 2 H), 8.04-7.99 (m, 2 H), 7.96 (s, 1 H), 7.66-7.60 (m, 3 H), 7.52-7.48 (m, 2 H), 6.40 (s, 1 H), 3.57 (s, 3 H), 2.40 (s, 3 H), 1.56-1.50 (m, 2 H), 1.31-1.25 (m, 2 H); ESI-MS: m/z 427.4 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH2:16][CH:15]2[C:18](OC)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>CCOCC>[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH2:16][CH:15]2[CH2:18][OH:19])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCC1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a suspension of 0.57 g of lithium aluminium hydride in 30 ml of dry ether is dropwise added a solution of 6 g (0.021 mole) of 1-diphenylmethyl-2-methoxycarbonylazetidine [prepared in the manner described in J. Heterocyclic Chem., 6, 435 (1969) by R. M. Rodebaugh and N. H. Cromwell] in 30 ml of dry ether in a period of 15 minutes, and the mixture is stirred at room temperature for 15 minutes. The excess amount of lithium aluminium hydride is decomposed with ethyl acetate. The insoluble materials are filtered off and washed with dry ether. The combined filtrate and washings are evaporated to dryness under reduced pressure. The residue is dissolved in ether and the resulting solution is evaporated to yield 4.7 g of crude syrupy 1-diphenylmethyl-2-hydroxymethylazetidine in 90% yield.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH3:34])[N:33]=[C:29]5[C:28]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=6[C:48]6[N:52](C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)[N:51]=[N:50][N:49]=6)=[CH:38][CH:37]=5)=[C:27]4[CH2:72][CH2:73][CH3:74])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)C=CC=CC=1>C1(C)C=CC=CC=1>[NH:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]3[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[C:28]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[NH:49][N:50]=[N:51][N:52]=5)=[CH:38][CH:37]=4)=[C:27]3[CH2:72][CH2:73][CH3:74])=[CH:23][CH:24]=2)=[N:8][N:9]=[N:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A 342 mg portion of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-methyl-6-propyl-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 1a) was treated in the same manner as described in Example 12, the resulting residue was mixed with toluene and heated under reflux and then the solution was cooled spontaneously to collect the thus formed precipitate by filtration, thereby giving 182 mg of 5,7-bis[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-methyl- 6-propyl-5H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:23]4[C:22](=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=4)[NH:25][C:9]=3[C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3ccc([N+](=O)[O-])cc3c1C2

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound A2 and 4-nitrophenylhydrazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[O:10][CH2:11][C:12]([F:25])([F:24])[C@:13]([C@H:16]2[CH2:18][C@@H:17]2[C:19]([O:21]CC)=[O:20])([CH3:15])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[O:10][CH2:11][C:12]([F:24])([F:25])[C@:13]([C@H:16]2[CH2:18][C@@H:17]2[C:19]([OH:21])=[O:20])([CH3:15])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OCC1(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)([C@H]2C[C@@H]2C(=O)O)C(F)(F)CO1
Yield: 64.1 %

Procedure:
A solution of (1S,2S)-rel-ethyl 2-((R)-2-(bis(tert-butoxycarbonyl)amino)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)cyclopropanecarboxylate (519 mg, 1.12 mmol) in ethanol (10 ml) and sodium hydroxide (2M; 2.24 ml, 4.49 mmol) was heated at 40° C. for 90 minutes. Thereafter hydrochloric acid (1N) was added dropwise under cooling with ice until a neutral pH was reached. For the workup, the solvent was removed at reduced pressure, the residue taken up in water and dichloromethane, and the mixture acidified by dropwise addition of hydrochloric acid (1N) under cooling with ice. The aqueous layer which was extracted 3 times with dichloromethane, then sodium chloride was added to the aqueous layer which was extracted again 3 times with dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated at reduced pressure to give the crude (1S,2S)-rel-2-((R)-2-tert-butoxycarbonylamino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropane-carboxylic acid (240 mg, 64% yield) which was used in the next step without further purification. MS (ISP): m/z=335.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][C:10](=[CH2:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B.C1C[O:25]CC1.C([O-])(O)=O.[Na+].OO>O1CCCC1.CCOC(C)=O.O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][OH:25])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reactant: C1CCOC1
Agent: B
Agent: O=C([O-])O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2CO
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.100 g, 0.35 mmol) in tetrahydrofuran (1 mL) was treated with BH3-THF complex (0.36 mL, 1M in THF), and stirred for 30 min. at 20° C. Water (0.5 mL), saturated aqueous NaHCO3 (0.5 mL), and 30% H2O2 (0.2 mL) were added sequentially and the reaction stirred for 30 min. at 20° C. The product mixture was diluted with EtOAc (10 mL), washed with brine (10 mL), and concentrated. Flash chromatography (33% EtOAc in hexane, silica) resulted in 0.035 g of a clear oil. MS calculated for C14H16F3NO3+H: 304, observed: 304.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:39])[NH:28][S:29]([CH2:32][CH2:33][CH2:34][O:35]C(=O)C)(=[O:31])=[O:30])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:39])[NH:28][S:29]([CH2:32][CH2:33][CH2:34][OH:35])(=[O:31])=[O:30])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:40][CH:41]=1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)NS(=O)(=O)CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a mixture of 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (200 mg), THF (3 mL), and methanol (3 mL) was added a 1 M aqueous sodium hydroxide solution (1.7 mL), followed by stirring at room temperature overnight. The reaction mixture was adjusted to pH 4 by adding 1 M hydrochloric acid (1.7 mL), and further, water (20 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water (4 mL), and then washed with cold ethanol (3 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-hydroxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (80 mg) as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][NH:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[C:19]=[O:20]>C(Cl)Cl>[NH:7]([C:8]1[N:9]=[CH:10][C:11]2[CH2:17][N:16]([C:19]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:15][CH2:14][C:12]=2[N:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1cccnc1
Reactant: c1ccc(Nc2ncc3c(n2)CCNC3)cc1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CCc2nc(Nc3ccccc3)ncc2C1

Procedure:
A solution of N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 6 (75 mg, 0.33 mmol), 3-isocyanatopyridine (41.8 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 1 hour. After 1 hour the reaction mixture was diluted with CH2Cl2 and washed with sat. aqueous NaHCO3(aq). The organic phase was collected, dried and concentrated. The residue was dissolved in CH2Cl2 and washed with 3% aqueous LiCl solution and water. The organic phase was collected, dried and concentrated to give the title compound (45.9 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14]
Reactant: [H][H]
Reactant: Cc1ccccc1C(=O)c1nc[nH]c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccccc1Cc1nc[nH]c1C

Procedure:
2.1 g of 5-methyl-4-(2'-methylbenzoyl)imidazole are dissolved in 10 ml of acetic acid. 0.2 g of 10% palladium-on-carbon is added and the reaction mixture is agitated vigorously at about 60° C. in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is then cooled and filtered and the filtrate is evaporated to dryness. The residue is dissolved in 20 ml of water and the resultant solution is made alkaline (pH about 10) with sodium hydroxide. The precipitate which forms is removed by filtration, washed with water and dried. The product is transformed to the hydrochloride in isopropanol, its melting point after recrystallization from water-ethanol being 226°-268° C. The free base, 5-methyl-4-(2'-methylbenzyl)imidazole, which is liberated from the hydrochloride in water with sodium hydroxide, has a melting point of 138°-140° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[C:12]([NH2:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][S:9]1.[OH-].[Na+]>CO>[NH2:13][C:12]1[CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:18])=[O:2])[S:9][CH2:10][C:11]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCC1SCC(C(=O)OC)=C1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(N)C(CCCCC(=O)O)SC1
Yield: 71 %

Procedure:
To a solution of 27.3 g (.1 mole) of 3-amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid methyl ester in 250 ml dry methanol was added 4.0 g (0.1 mole) of sodium hydroxide pellets. The reaction mixture was refluxed 4.0 hrs, cooled and concentrated to a volume of 50 ml. The residue was taken up in 80 ml dichloromethane and transfered to a separatory funnel. After the addition of 150 ml of 10% by weight aqueous sodium bicarbonate solution, the aqueous layer was extracted twice with 50 ml portions of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to yield 6.4 g (0.0234 mole) of recovered starting material. The aqueous phase was adjusted to pH 1 with 6 N hydrochloric acid and extracted three times with 75 ml portions of dichloromethane. The organic phases were pooled, dried over anhydrous sodium sulfate, and evaporated to yield 18.3 g (0.071 mole, 71%) of 3-amino- 4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid as a tan solid, upon trituration with pet. ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][CH:26]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:27]\[C:22]3[C:21]([C:20]([F:29])([F:19])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=Cc1ncccc1C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ncccc1C(F)(F)F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (250 mg, 1.010 mmol) in toluene 10 mL was added 3-(trifluoromethyl) picolinaldehyde (177.0 mg, 1.010 mmol). PTSA (384.5 mg, 2.021 mmol) was added to the reaction mixture and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-6-methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methylene)-2,3-dihydro-1H-inden-1-one 67. The compound 67 was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 34% ethyl acetate in hexane to afford yellow coloured solid.