Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Br[C:8]1[N:33]=[C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]3[S:26][CH:27]=[C:28]([CH:30]([F:32])[F:31])[N:29]=3)=[O:18])[CH:14]=[CH:15][N:10]2[N:9]=1>C(OCC)(=O)C>[F:32][CH:30]([F:31])[C:28]1[N:29]=[C:25]([C:20]2[CH:21]=[N:22][N:23]([CH3:24])[C:19]=2[C:17]([NH:16][C:13]2[CH:14]=[CH:15][N:10]3[N:9]=[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[N:33]=[C:11]3[CH:12]=2)=[O:18])[S:26][CH:27]=1
Reactant: Cn1ncc(-c2nc(C(F)F)cs2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C[C@H]1CCCN1
Solvent: CCOC(C)=O
Product: C[C@H]1CCCN1c1nc2cc(NC(=O)c3c(-c4nc(C(F)F)cs4)cnn3C)ccn2n1
Temperature: 150 °C

Procedure:
An (S)-2-methylpyrrolidine (0.5 ml) solution of the N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg) synthesized in (Example 3.15) <Step 6> was stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (20 ml) was added to the reaction solution, and the mixed solution was successively washed with water (15 ml) twice and with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=40:60), so as to obtain the title compound (13 mg) in the form of a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:26]=1[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[C:37]([C:39]3[C:47]4[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=4)[N:41]([CH3:52])[CH:40]=3)=[CH:38][C:31]=12.O>ClCCl>[CH3:23][O:24][C:25]1[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:26]=1[CH2:27][N:28]([CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:53]([C:56]3[CH:57]=[CH:58][C:59]([CH3:62])=[CH:60][CH:61]=3)(=[O:55])=[O:54])[C:37]([C:39]3[C:47]4[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=4)[N:41]([CH3:52])[CH:40]=3)=[CH:38][C:31]=12)[S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]([F:22])([F:21])[F:8])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c(OC)c1
Reaction time: 24 h

Procedure:
0.052 cm3 of triethylamine and 0.265 cm3 of 4-(trifluoromethoxy)benzenesulfonyl chloride are added to a solution of 0.200 g of (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 6 cm3 of dichloromethane, under an argon atmosphere, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours. 2 cm3 of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.210 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide is obtained, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:54].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:54][C:40]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]4)=[CH:44][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 175 °C
Yield: 80 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.20 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (Example 173, step B) (49 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (99 μL, 0.40 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 minutes, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 minutes, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (120 mg, 0.16 mmol, 85%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.36 (br s, 1H), 8.45 (s, 1H), 8.20 (d, 1H, J=5.31 Hz), 8.05 (m, 1H), 7.74 (m, 1H), 7.69 (d, 1H, J=8.97 Hz), 7.34-7.46 (m, 3H), 7.27 (d, 1H, J=8.61 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.95 (t, 1H, J=6.68 Hz), 6.68 (d, 1H, J=2.01 Hz), 6.53 (d, 1H, J=5.13 Hz), 6.48 (dd, 1H, J=2.20 and 8.61 Hz), 6.24-6.30 (m, 2H), 3.80 (s, 3H), 3.11-3.16 (m, 4H), 2.45-2.54 (m, 4H), 2.28 (t, 2H, J=7.42 Hz), 1.41-1.50 (m, 4H), 0.87 (t, 3H, J=7.42 Hz). MS (ESI): 719 [M+H]+.
Reaction SMILES: C[O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1.COCC1NC(C2C(C)=CC(C)=C(C=2)C(N2CCC(C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1>>[OH:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[O:14])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Agent: COCc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CO)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 3, except 4-(1-(3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 11) was used in place of 4414542-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 2). m/z (ES+) 415 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][CH2:17][S:18]([N:21]2[CH2:40][CH2:39][C:24]3([N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][C:32](=[C:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]4)[NH:26][C:25]3=[O:38])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[C:11]([CH3:41])[CH:10]=1)C)(C)(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:15][C:13]1[CH:14]=[C:9]([NH:7][CH3:6])[CH:10]=[C:11]([CH3:41])[C:12]=1[CH2:16][CH2:17][S:18]([N:21]1[CH2:22][CH2:23][C:24]2([N:28]=[C:27]([CH:29]3[CH2:34][CH2:33][C:32](=[C:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)[NH:26][C:25]2=[O:38])[CH2:39][CH2:40]1)(=[O:19])=[O:20]
Reactant: CC(C)=C1CCC(C2=NC3(CCN(S(=O)(=O)CCc4c(C)cc(N(C)C(=O)OC(C)(C)C)cc4C)CC3)C(=O)N2)CC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CNc1cc(C)c(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCC(=C(C)C)CC2)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
About 40 4AMS beads were added to a solution of (4-{2-[2-(4-isopropylidene-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (85.7 mg, 143 μmol) in dichloromethane (1.4 ml), and the mixture was stirred at room temperature for 10 minutes. Thereafter, BF3.Et2O (90.2 μl, 715 μmol) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for three hours. The reaction mixture was quenched by adding triethylamine and diluted with ethyl acetate. The organic layer was then washed with a saturated aqueous sodium bicarbonate solution and water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0→92/8) to give 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-(4-isopropylidene-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (66.0 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([O:15][C:22]3[N:23]([CH3:33])[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[N:25][N:26]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1nnn(-c2cccc(Cl)c2)n1
Yield: 47.5 %

Procedure:
The title compound (44.0 mg, 48%, clear oil) was prepared from 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (54.3 mg, 0.242 mmol), sodium hydride (12.0 mg, 0.29 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (69.1 mg, 0.29 mmol). 1H NMR (CDCl3) δ (ppm): 8.75 (m, 2H), 8.16 (m, 1H), 8.04 (m, 1H), 7.61 (m, 2H), 7.49 (m, 2H), 6.59 (q, 1H), 3.63 (s, 3H), 2.04 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH:29]=O)[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH2:29][NH:13][C@H:10]1[CH2:9][CH2:8][C@@H:7]([N:6]3[C:5]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=4[N:3]=[C:2]3[CH3:1])[CH2:12][CH2:11]1)[CH2:23]2
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H30ClN3 (m/e) calcd 407.2128, obsd 408.2 (M+H).
Reaction SMILES: C([OH:23])CCCCCCCCCCCCCCCCCCCCC.[CH3:24][CH:25]([CH2:27][CH2:28][CH2:29][C@H:30]([CH2:32][CH2:33][CH2:34][C@H:35]([CH2:37][CH2:38][CH2:39]/[C:40](=[CH:42]/[CH2:43]O)/[CH3:41])[CH3:36])[CH3:31])[CH3:26]>>[CH3:41][C:40]([OH:23])([CH2:39][CH2:38][CH:37]=[C:35]([CH3:36])[CH2:34][CH2:33][CH:32]=[C:30]([CH3:31])[CH2:29][CH2:28][CH:27]=[C:25]([CH3:26])[CH3:24])[CH:42]=[CH2:43]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Compound U ##STR47## docosanol Compound V ##STR48## phytol Control compound: -MDP (AcMur-L-Ala-D-Glu)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:37]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:35][C@:36]([OH:37])([C:38]4[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=4)[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc([N+](=O)[O-])cc1)CO3
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
(S)-6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (3.3 g) and potassium carbonate (2 g) were stirred together in a flask containing 25 mL anhydrous acetone at room temperature under nitrogen atmosphere. After 15 minutes, 2-bromo-1-(4-nitro-phenyl)-ethanone (3.2 g) was added and the mixture was stirred at 60-80° C. for 6 hours. The reaction mixture was diluted with 50 mL of water and 100 mL of ethyl acetate and the layers were separated. The organic layer was washed with water three times and brine once, dried over sodium sulfate and concentrated to provide (S)-3-hydroxy-3-(4-nitro-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (3.1 g), and was dissolved in 25 mL of 1:1 ratio of anhydrous triethylamine and dichloromethane under nitrogen atmosphere. The reaction mixture was cooled to −76 to −40° C. and methanesulfonyl chloride (1.9 g) was added dropwise to maintain internal temperature below −30 to −40° C. The reaction mixture was allowed to warm to room temperature gradually (8-10 hours) and was quenched with 1M sodium carbonate solution (10 mL) and extracted with dichloromethane three times (3×25 mL). The organic layers were washed with water, brine and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography and eluted with 7:3 hexanes/EtOAc to give a regioisomeric mixture of (S)-3-(4-Nitro-phenyl)-8,9-dihydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (2.0 g). LCMS: (m/z) 469, 1H NMR (400 MHz, Acetone-d6): 8.12 (d, 1H), 7.61 (d, 1H), 7.15 (m, 1H), 6.78-6.69 (m, 1H), 5.01-511 (m, 1H), 4.94-4.87 (m, 1H), 4.91-4.81 (m, 1H), 4.64-4.49 (m, 1H), 4.43-4.29 (m, 1H), 3.65-3.58 (m, 3H), 3.18-2.99 (m, 2H), 1.53-1.40 (m, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5].[C:17](=N)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:18]1([C:17](=[N:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:5])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)NCCCCc1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN=C(c1ccccc1)c1ccccc1)NCCCCc1ccccc1

Procedure:
2-Amino-N-(4-phenyl-butyl)-acetamide-hydrogen chloride salt is stirred with benzophenone imine (12.6 mL, 75 mmol) in CH2Cl2 (200 mL) for 24 h. The organics are then washed with water, dried (MgSO4), and concentrated to provide 2-(diphenylmethylenamino)-N-(4-phenyl-butyl)-acetamide (7) as a white solid which is used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][N:11]([CH2:19][C@H:20]([OH:32])[C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.[F:40][C:41]([F:56])([F:55])[C:42]([N:44]1[CH2:49][C:48]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[O:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>C(#N)C>[OH:32][C@H:20]([C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[CH2:19][N:11]([CH2:10][CH2:9][S:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:52]1[CH2:53][CH2:54][C:48]2([O:47][CH2:46][CH2:45][N:44]([C:42](=[O:43])[C:41]([F:40])([F:55])[F:56])[CH2:49]2)[CH2:50][CH2:51]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCSCCCCCCBr)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C

Procedure:
(R)-tert-Butyl 2-(6-bromohexylthio)ethyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 101, step c) (0.55 g) was combined with 2,2,2-trifluoro-1-(1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-ethanone trifluoroacetic acid salt (example 101, step e) (0.25 g) and triethylamine (0.26 mL) in acetonitrile (20 mL) and heated at 80° C. for 48 h. The volatiles were evaporated in vacuo. Purification was achieved by silica gel chromatography eluting with 10% MeOH in DCM to give the subtitled compound as a yellow gum. Yield 0.10 g and 0.074 g (less pure).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1([CH3:23])[N:18]2[C:19](=[O:22])[CH2:20][CH2:21][C@@H:17]2[CH2:16][O:15]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[F:34][C@H:20]1[C:19](=[O:22])[N:18]2[C:14]([CH3:23])([CH3:13])[O:15][CH2:16][CH:17]2[CH2:21]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)OCC2C[C@@H](F)C(=O)N21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture consisting of diisopropylamine (6.5 mL, 46 mmol) and THF (75 mL) at −78° C. was added dropwise a solution of nBuLi (2.5 M in hexanes, 18 mL, 44 mmol), and the resulting solution stirred for one hour. A solution consisting of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 4, 3.6 g, 23 mmol) in THF (25 mL) was added dropwise, and the resulting solution stirred for one hour. A solution consisting of N-fluorobenzenesulfonimide (9.5 g, 30 mmol) in THF (50 mL) was added dropwise, and the resulting solution was allowed to stir for 75 minutes below −55° C., and was subsequently quenched with the addition of a saturated aqueous ammonium chloride solution and warmed to room temperature. The organic material was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated to a gold oil, which was purified by silica gel chromatography. Elution with ethyl acetate:heptanes (1:3 v/v) afforded an approximately 1:1 mixture of the diastereomers of the title intermediate (1.54 g) as a clear oil; TLC Rf 0.40 (solvent system 50:50 v/v heptanes:ethyl acetate); 1H-NMR (CDCl3) δ 5.4-5.2 (m, 1H), 5.2-5.0 (m, 1H), 4.5-4.4 (m, 1H), 4.2-4.1 (m, 2H), 4.0-3.9 (m, 1H), 3.5 (t, 1H), 3.4 (t, 1H), 2.8-2.7 (m, 1H), 2.5-2.3 (m, 1H), 2.1-1.8 (m, 2H), 1.7 (s, 3H), 1.7 (s, 3H), 1.5 (s, 3H) 1.5 (s, 3H); 19F-NMR (CDCl3, 376 MHz) δ −102.2 (dd, ˜0.5F, J=264.2, 13.2 Hz), ˜103.5 (ddd, ˜0.5F, J=264.3, 26.5, 14.6 Hz); MS (ESI+) m/z 174.1 (M+1).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[F:14][C:15]([F:33])([F:32])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19]4[CH:20]=[N:21][C:16]([C:15]([F:33])([F:14])[F:32])=[N:17][CH:18]=4)[CH:23]=3)[CH2:28]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: FC(F)(F)c1ncc(-c2ccc3c(c2)CCNC3)cn1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C(F)(F)F)nc4)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.0295 g, 0.13 mmol) in dry THF (0.60 mL) was added dropwise to a stirred solution of 6-[2-(trifluoromethyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline (0.039 g, 0.14 mmol), DIPEA (0.034 mL, 0.20 mmol) and dry THF (0.60 mL) at ice-bath temperature. After the addition was complete the solution was stirred at RT for 2 h and then taken up in water-brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give a crude product. Purification by preparative HPLC afforded 0.050 g (76%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][C:12]2([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].Cl>C(Cl)Cl>[CH3:41][S:42]([O:31][CH2:30][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][C:12]2([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2CC3(CCCC(CO)(COCc4ccccc4)C3)OC2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(COS(C)(=O)=O)C3)OC2=O)cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-((benzyloxy)methyl)-7-(hydroxymethyl)-3-(4-methoxybenzyl)-1-oxa-3-azaspiro[4.5]decan-2-one (5.26 g, 12.36 mmol) in DCM (56 mL) at RT was added DIEA (4.32 mL, 24.7 mmol) and methanesulfonyl chloride (1.25 mL, 16.1 mmol). After 1 h, 2N HCl (100 mL) was added to the reaction. The layers were separated, and the aqueous layer was washed with DCM (100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified on a 80 g silica gel column (10-70% EtOAc/hexanes, 30 min gradient; 70% EtOAc/hexanes, 5 min; 60 mL/min elution; 254 nm detection) to afford (3-{[4-(Methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl methanesulfonate (5.71 g, 87% yield). MS (m/z) 504.2 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=O.[NH2:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH2:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCOCC1>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH2:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CC(C)C[C@H](N)C(=O)NCC(N)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)c1ccc[nH]1)C(=O)NCC(N)=O
Reaction time: 2 h

Procedure:
7.0 ml of triethylamine and 10.4 g of the N-hydroxysuccinimide ester of pyrrole-2-carboxylic acid were added to 9.4 g of L-leucyl-glycinamide in 120 ml of dioxane at 10° C. and the reaction mixture was stirred for 2 hours at this temperature, after which 30 ml of water were added and the stirred mixture was allowed to react for 20 hours at room temperature.