Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[C:51]1([CH2:57][CH:58]([C:60]2[N:64]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[N:63]=[N:62][CH:61]=2)[NH2:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[C:51]1([CH2:57][CH:58]([NH:59][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[C:60]2[N:64]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[N:63]=[N:62][CH:61]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired compound. 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=7.9 Hz, 1H), 7.96 (s, 1H), 7.58-7.42 (m, 3H), 7.30-7.18 (m, 2H), 7.18-7.06 (m, 3H), 7.00-6.86 (m, 2H), 5.06 (q, J=7.6 Hz, 1H), 4.74-4.61 (m, 2H), 2.98 (td, J=13.6, 6.4 Hz, 2H), 2.43 (s, 2H), 2.37-2.17 (m, 2H), 1.61 (d, J=5.9 Hz, 4H). MS (m/z) 495 [M+H]+.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:22]2[N:21]=[C:20]([N:6]3[C:14]4[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH:25]=[CH:24][N:23]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(C#N)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-n3ccc4cc(C#N)ccc43)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-indole-5-carbonitrile (prepared by TBDMS protection of 1H-indole-5-carbonitrile using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 441 mg (26%)
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][O:14][CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.BrC1NC2N=CN=C([C:26]3[C:27]([CH3:45])=[C:28]([NH:32][C:33](=[O:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][CH:31]=3)C=2C=1>>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH2:12][CH2:13][O:14][CH2:15][CH:16]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[C:27]=2[CH3:45])=[O:44])=[CH:35][CH:36]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(Br)cc12
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 64 was prepared analogue to Intermediate 11 by replacing 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine with Intermediate 54.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH:19]=[CH2:20])=[CH:12][N:11]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:9][C:10]1[N:11]=[C:12]2[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH2:19][CH2:20][N:1]2[CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:14][N:15]=1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Reactant: CN1CCC(N)CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 200 mg, 1.74 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. for 3 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 0-5% 2M ammonia in MeOH/DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow solid (39 mg)
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:14])[C:5]1[N:28]([CH2:29][C@H:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: O=CCC1Cc2cc(F)c(F)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)c(F)cc1C2
Reaction time: 0.75 h
Yield: 45.4 %

Procedure:
A solution of 2.1 g of (RS)-2-(2-oxoethyl)-5,6-difluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.13 g (45%) of (R)-1-(6,7-difluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown solid which was used without further recrystallization in the next reaction.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].II.[CH2:13]([C:16](=[CH2:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH3:15].C(N(CC)CC)C>O.ClCCl>[CH3:20][O:19][C:17](=[O:18])/[C:16](/[CH2:13][CH2:14][CH3:15])=[CH:21]/[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(CCC)C(=O)OC
Agent: II
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Sodium benzenesulfinate (11.21 g, 68.27 mmol) was dissolved in water (100 ml). This solution was shaken with iodine (17.33 g, 68.27 mmol) in dichloromethane (100 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulphate and filtered into a flask containing methy 2-propylacrylate (5.0 g, 39.01 mmol). The solution was stired overnight at room temperature and then cooled to 0° C. Triethylamine (11 ml, 78.01 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. The mixture was diluted with water and the organic layer was washed with 1N hydrochloric acid (75 ml), 10% aqueous sodium bisulfite (75 ml), and brine, then dried over magnesium sulfate, filtered and evaporated to give (E)-3-benzenesulfonyl-2-propylacrylic acid methyl ester (9.1 g, 87% yield).
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
compound NR40. N-Boc-Tyr(Bn)-Ala-Trp-OMe (119 mg, 0.185 mmol) in solution in MeOH (4 mL) was hydrogenated overnight at atmospheric pressure in the presence of 10% Pd on charcoal (30 mg). After filtration, evaporation of the solvent and trituration with ether, N-Boc-Tyr-Ala-Trp-OMe (77 mg, 76%) was obtained as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.19 (d, J=7 Hz, 3H, CH3), 1.29 (s, 9H, (CH3)3), 2.55 and 2.80 (ABX system, 2H, CH2β), 3.13 and 3.16 (ABX system, 2H, CH2β), 3.55 (s, 3H, OCH3), 4.05 (m, 1H, CHα), 4.35 (m, 1H, CHα), 4.50 (m, 1H, CHα), 6.63 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.6 Hz, 1H), 7.03 (m, 4H), 7.16 (d, J=2.1 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H, NH), 8.32 (d, J=7.3 Hz, 1H, NH), 9.14 (s, 1H, OH), 10.86 (s, 1NH). 13C NMR (75 MHz, DMSO-d6) δ 18.4 (CH3); 26.9 (CH2 Trp), 28.1 ((CH3)3), 36.4 (CH2 Tyr), 47.8, 51.7, 53.0, 55.9 (CHα Ala, Tyr, Trp or OCH3), 77.9 (C(CH3)3), 109.1 (aromatic C), 111.4, 114.8, 117.9, 118.4, 120.9, 123.7 (aromatic CH), 127.0, 128.2 (aromatic C), 130.0 (aromatic CH), 136.0 (aromatic C), 155.2, 156.6 (Car-O or CO carbamate), 171.4, 172.0, 172.2 (2 CO amide or CO ester). Anal. Calcd. for C29H36N4O7, 1H2O: C, 61.04; H, 6.71; N, 9.82. Found: C, 61.02; H, 6.62; N, 9.66. HRMS (ESI) calcd for C29H36N4O7Na [(M+Na)+] 575.2482. Found 575.2480.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:7]([C:14]#[N:15])[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 2 h

Procedure:
42 mg of 6-methoxy-1-oxo-4-(3-fluorophenyl)-1,2-dihydroisoquinoline-3-carbonitrile in 3 mL POCl3 was heated from room temp to 80 C. After 2 h, the temperature was raised to 90 C, and heating was continued for 20 h. The reaction was concentrated, redissolved in EtOAc, cooled to 0 C, and saturated aqueous sodium bicarbonate was added dropwise to quench the remaining reagent. The mixture was separated, and the aqueous solution was extracted with EtOAc (3×). The combined organic solutions were dried over MgSO4 and concentrated. Flash chromatography (3% to 30% EtOAc in hexanes) gave a white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(OC(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(OC(F)(F)F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC(F)(F)Oc1cccc(NCC2CCCC2)c1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(OC(F)(F)F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-trifluoromethoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:21]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (0.852 g, 6.21 mmol), Et3N (0.952 mL, 6.83 mmol), DMAP (76 mg, 0.621 mmol) in CH2Cl2 (10 mL) at 0° C. was added 2-chloroacetyl chloride (0519 mL, 6.52 mmol), and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was washed with aqueous HCl (1 M, 20 mL), then sat. NaHCO3 (20 mL), dried (Na2SO4), concentrated, further dried under high vacuum and (S)-2-chloro-N-(2-hydroxy-1-phenylethyl)acetamide (0.60 g, 45.2% yield) was obtained as white solid. LCMS (m/z): 214 (MH+), 0.44 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.C[Si]([CH:34]=[N+:35]=[N-:36])(C)C.O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:35](=[CH:34][C:12]([C@@H:9]1[CH2:10][CH2:11][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[N-:36]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.80 g, 8.95 mmol) in tetrahydrofuran (90.0 mL) was cooled to 0° C., and isobutyl chloroformate (1.30 mL, 9.85 mmol) and triethylamine (1.50 mL, 10.7 mmol) were added. After stirring for 1 hour at room temperature, ammonium salt was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (90.0 mL), and trimethylsilyldiazomethane (13.5 mL, 26.8 mmol) was added. After stirring for 7 hours at room temperature, to the mixture were added saturated sodium bicarbonate water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate=90/10 to 75/25) to give the title compound (1.40 g, 6.22 mmol, 69%).
Reaction SMILES: [F:1][C:2]1[C:3](/[CH:8]=[N:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C@H:29]1[C@@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:30]1=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(/N=C/c2ncccc2F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A solution (2.29 l) of N-[(E)-(3-fluoro-2-pyridyl)methylidene]-4-methoxyaniline (449 g) and triethylamine (204 g) in dichloromethane was cooled to −10° C. Then acetoxyacetyl chloride (250 g) was added dropwise thereinto and the resultant mixture was stirred at the same temperature for 30 minutes. Then it was heated to room temperature and stirred for 16 hours. The liquid reaction mixture was washed with water and the solvent was concentrated under reduced pressure to thereby give a crude product (723 g). This crude product was recrystallized from a solvent mixture of ethanol (6.9 l) and ethyl acetate (350 ml) to thereby give the title compound (486 g) as brown crystals.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][S:6][C:7]1[S:8][C:9]([NH:12][C:13]([N:15]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:10][N:11]=1)C.C1(NC2CCCC2)CCCC1.C(OC(=O)CSC1SC(N)=NN=1)C>>[CH:21]1([N:15]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:9]2[S:8][C:7]([S:6][CH2:5][C:4]([OH:26])=[O:3])=[N:11][N:10]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)CSc1nnc(NC(=O)N(C2CCCC2)C2CCCC2)s1
Agent: C1CCC(NC2CCCC2)C1
Agent: CCOC(=O)CSc1nnc(N)s1
Product: O=C(O)CSc1nnc(NC(=O)N(C2CCCC2)C2CCCC2)s1

Procedure:
[5-(3,3-Dicyclopentyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-acetic acid ethyl ester prepared as described in general procedures (A) and (B) using dicyclopentylamine and ethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:27]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH2:39]Cl)=[N:25][C:20]=3[CH:21]=[N:22][C:23]=2[CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]3[N:27]4[CH2:28][CH2:29][CH2:30][N:31]([C:32]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38])[CH2:39][C:26]4=[N:25][C:20]=3[CH:21]=[N:22]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
Under a nitrogen atmosphere, potassium tert-butoxide (142.7 mL of a 1 M solution in THF) was added to a solution of tert-butyl 3-[7-benzyloxy-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (57.2 g, 118.9 mmol) in THF (142.7 mL). After the reaction was stirred at ambient temperature for ten minutes, additional potassium tert-butoxide (32 mL of a 1 M solution in THF) was added. The reaction was stirred overnight at ambient temperature and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 67-minute gradient from 0:100 to 3:97) and recrystallized sequentially from dichloromethane and acetonitrile to provide 26.99 g of tert-butyl 3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:18]2)[NH:14][CH2:13][CH:12]3[CH3:31])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(O[BH-](O[C:42](=O)[CH3:43])OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH2:18]2)[N:14]([CH2:2][CH2:1][CH2:3][C:42]2[CH:43]=[CH:9][CH:10]=[CH:5][CH:6]=2)[CH2:13][CH:12]3[CH3:31])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)NCC3C)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(CCCc2ccccc2)CC3C)c1

Procedure:
2-[5-(3-Isopropoxy-phenyl)-4-methyl-2-aza-bicyclo[3.3.1]non-7-yl]-isoindole-1,3-dione (2.92 g, 7.0 mmol) and hydrocinamaldehyde (1.12 g, 8.3 mmol) were dissolved in dichloroethane (115 ml) followed by the addition of sodium triacetoxyborohydride (2.1 g, 9.7 mmol) and allowed to react at room temperature overnight. The reaction was quenched with the addition of a saturated sodium bicarbonate solution (200 ml) and the organic layer separated. The aqueous was then extracted with CHCl3. The combined organic fractions were dried (NaSO4), filtered, and concentrated in vaccu. The crude product was then purified by flash chromatography on an aluminum oxide (neutral, Brockman activity II-III) column and eluting with 8:2 hexane:ethyl acetate giving 3.16 g (83.9%) of the desired product. 1H NMR (CDCl3) δ 7.75 (m, 2H), 7.64 (m, 2H), 7.25 (m, 5H), 6.79 (m, 2H), 6.68 (d, J=7.8, 1H), 5.15 (m, 1H), 4.52 (sept., J=6.0 Hz, 1H), 3.27 (br, 1H), 3.08 (dd, J1=6 Hz, J2=3 Hz, 1H), 2.78-2.52 (m, 6H), 2.25-2.16 (m, 5H), 1.96-1.78 (m, 4H), 1.31 (d, J=6, 6H), 0.78 (d J=6.9, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(O)cc21
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-6-methoxyindan (6.40 g, 27.4 mmol) in dichloromethane (150 ml) was added dropwise, under ice-cooling, boron tribromide (5.19 ml, 54.8 mmol). The mixture was then stirred for one hour. The reaction mixture was poured into water. The mixture was stirred for 8 hours at room temperature, which was subjected to extraction with chloroform. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give 4.70 g (yield 78%) of the above-titled compound, m.p.107-108° C.