Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1.C(N(CC)CC)C.[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C

Procedure:
6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (4; 0.39 g, 0.86 mmol) was completely dissolved in DMF (15 mL) with gentle warming. After cooling the solution to room temperature without reprecipitation, it was mixed with triethylamine (Et3N; 0.52 g, 5.15 mmol) followed by the addition of 5 (0.25 g, 1.14 mmol) in DMF (3 mL) dropwise while stirring. After overnight reaction at room temperature, the mixture was filtered, evaporated in vacuo, and loaded to a silica column for further purification. The products were separated by eluting with mobile phases of 5-20% MeOH in DCM to afford 6 (0.45 g; 93.8%) as a yellowish solid. 1H NMR (400 MHz) (CD3OD) δ: 4.53 (t, 1H, CHN), 4.34 (t, 1H, CHN), 3.25 (dd, 1H, CHS), 3.20 (t, 2H, CH2NH), 3.08 (t, 2H, CH2NH), 2.96 (d, 1H, CHHS), 2.73 (d, 1H, CHHS), 2.22 (t, 4H, CH2CO), 1.38-1.80 (m, 29H). 13C NMR (100.67 MHz) (DMSO) δ: 176.02, 175.97, 166.05, 158.50, 79.50, 63.39, 61.63, 57.01, 41.24, 41.04, 40.24, 36.99, 36.82, 30.90, 30.35, 30.13, 29.78, 29.49, 28.80, 27.56, 26.92, 26.74. HRMS (ESI) calculated for C27H49N5O5S, [M+Na]+ 578.3352 (calcd.), 578.3349 (found).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CC(C)O
Product: Cc1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80° C. for 2 hours and evaporated under vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J=1.5, 7.2 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.60 (dd, J=1.5, 8.4 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.Cl[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][N:38]=1>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][N:38]=4)[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(C2)CN(c2ncnc4ccccc24)C3)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 4-chloroquinazoline (172 mg, 1 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated by evaporation and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). M+H+: 435.05.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2ccc(Cl)cc2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)CC(=O)NC2c1cccc(Cl)c1
Yield: 95 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.35 g, 0.97 mmol) prepared in example 9b was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.5 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(O)C.Cl.[NH2:19][OH:20]>CCCCCC>[OH:20]/[N:19]=[C:4](\[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)/C(=N/O)c1ccccc1C
Yield: 68 %

Procedure:
To a solution containing 19.2 g of ethyl 2-methylbenzoylformate (0.1 mol) and 100 ml of ethanol, 7.6 g of hydroxylamine hydrochloride (0.11 mol) was added and the resulting mixture was heated under reflux for 5 hours. Afterwards, the solvent was distilled off under reduced pressure as a work-up procedure to give a solid. The solid, to which hexane was added, was pulverized and 14.1 g of ethyl (E)-α-hydroxyimino-o-tolylacetate (yield; 68%) was filtered off. Furthermore, the concentrated residue of the filtrate, to which ethanol and a catalytic amount of thionyl chloride were added, was heated under reflux for 5 hours. The same work-up procedure as shown above was then employed to give 4.5 g of the objective product (yield; 21%). mp 88.0-89.0° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Nc1cnccn1
Product: Cc1ccc(Nc2cnccn2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using Aminopyrazine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=310.3 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[F:23]C1C=CC(COC(CC)=C)=CC=1OC1C=CC=CC=1>>[F:23][CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CC(C)(CCl)COCc1ccc(F)c(Oc2ccccc2)c1
Reactant: C=C(CC)OCc1ccc(F)c(Oc2ccccc2)c1
Product: CC(C)(CF)COCc1ccc(F)c(Oc2ccccc2)c1

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propy-1-yl p-toluenesulphonate (2.5 g), potassium fluoride (0.8 g) and tetraethylene glycol (7 cm3) was heated at 160° C. (under a drying tube to exclude moisture) for 3 hours. The reaction mixture was allowed to cool and stood at the ambient temperature for 17 hours. The mixture was poured into water and the products extracted into diethyl ether (2×200 cm3). The combined organic extracts were washed with water and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave an orange oil (1.5 g) which was passed through a short silica gel column using petroleum ether (boiling range 40°-60° C.) containing 10% by volume diethyl as eluent. Analysis of the resulting oil indicated 3 major components which were separated and isolated by high pressure liquid chromatography (eluting with hexane containing 1% by volume ethyl acetate). The first and third fractions were identified as 1-chloro-2,2-dimethyl-3-(4 -fluoro-3-phenoxybenzyloxy)propane (0.25 g--thought to have been formed owing to the presence of chloride ion contamination of the starting materials) and 2-(4-fluoro-3-phenoxybenzyloxy)-but-1-ene (an elimination by-product) respectively. The title compound (0.29 g) was obtained as the second eluted fraction; characterising data for this compound are given below:
Reaction SMILES: C(OC([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH:16]([CH3:17])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NCc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c21
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.33 (s, 1H) 8.06 (s, 1H) 7.94 (br. S., 2H) 7.57 (s, 1H) 7.42 (br. S., 2H) 7.12 (d, J=9.09 Hz, 1H) 6.75 (d, J=3.03 Hz, 1H) 4.70 (br. S., 1H) 4.10-4.22 (m, 2H) 1.60 (d, J=6.57 Hz, 3H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15](C1C=C(C)C=CC=1OC)([CH3:17])[CH3:16]>>[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH3:10])=[CH:5][C:6]=1[CH3:9])([CH3:17])[CH3:16]
Reactant: COc1ccc(C)cc1C
Reactant: COc1ccc(C)cc1C(C)(C)CC(=O)C(F)(F)F
Product: COc1cc(C(C)(C)CC(=O)C(F)(F)F)c(C)cc1C

Procedure:
The title product was prepared from 1-methoxy-2,4-dimethylbenzene according to the same procedure described in the synthesis of 1,1,1-trifluoro-4-(2-methoxy-5-methylphenyl)-4-methylpentan-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=[CH:13]1>>[Cl:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:15]2[N:14]=[CH:13][N:12]([CH3:11])[CH:16]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)cc(C)c1Cl
Reactant: Cn1cnc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1cc(-c2cn(C)cn2)cc(C)c1Cl

Procedure:
The title compound is prepared from 5-bromo-2-chloro-1,3-dimethyl-benzene and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:5]=1[C:6]([OH:8])=[O:7].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>O1CCCC1>[Cl:16][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
An ice-cooled suspension of 3.0 g (0.125 mol) of oil-free sodium hydride in 100 ml of tetrahydrofuran was treated portionwise during ten minutes with 12.2 g (0.052 mol) of 2,6-dichloro-3-nitrobenzoic acid [Lehmstedt and Schrader, Ber. 70B, 1526 (1937)]. After stirring for ten minutes, the suspension was treated dropwise with 7.0 g (0.05 mol) of 4-methoxybenzenethiol [C. M. Suter and H. L. Hansen, J. Am. Chem. Soc., 54, 4100 (1934)] in 50 ml of tetrahydrofuran. After stirring for 30 minutes at 0° C., the cooling bath was removed and the mixture was maintained at 25° C. for 12 hours. The mixture was acidified with 150 ml of 10% aqueous HCl, then treated with 200 ml of ethyl acetate. The organic layer was separated and the aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phases were dried (MgSO4), and concentrated to a yellow solid which was purified by flash chromatography on silica gel, utilizing dichloromethane:methanol (8:1) as eluting solvent, to give 11.9 g of 6-chloro-2-[(4-methoxyphenyl)thio]-3-nitrobenzoic acid, mp 154°-157° C., following crystallization from toluene.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:23](O)(=[O:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:23](=[O:25])[CH3:24])=[CH:16][N:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)O
Reactant: CC1(C)CCOc2ccc(C#Cc3ccc(CO)cn3)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1

Procedure:
A solution of 2.81 g (10 mmol) of 2-[2-(4,4-dimethylchroman-6-yl)ethynyl]-5-hydroxymethylpyridine, 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is then filtered and the residue washed with 50 ml of methylene chloride. The filtrate is then concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [Br-:1].[Li+].C[Si](Cl)(C)C.[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]O)[C:11]=2[O:10]1>C(#N)C.C(OCC)C>[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][Br:1])[C:11]=2[O:10]1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Reactant: [Br-]
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)Cc2cccc(CBr)c2O1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 8.7 grams (0.1 mole) of lithium bromide in 100 mL of acetonitrile is stirred, and 13.5 grams (0.125 mole) of trimethylsilyl chloride is added. Upon completion of addition, a solution of 8.9 grams (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol in 50 mL of acetonitrile is added. Upon completion of addition, the reaction mixture is warmed to reflux, where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature and then is taken up in 200 mL of diethyl ether. The mixture is then washed with 25 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, yielding 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl bromide.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[N:1]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1
Reactant: C1CC[C@H]2NCCN[C@H]2C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCNC2CCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To (4aR,8aS)-decahydroquinoxaline (1.4 g, 10 mmol) in dichloromethane (50 mL) was added triethylamine (1.7 mL, 12 mmol) followed by dropwise benzyl chloroformate (1.71 g, 10 mmol). The reaction mixture was stirred at room temperature for 2 h before being diluted with dichloromethane and washed with 1N NaOH followed by sat. aq. NH4Cl. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the crude product, which was purified via Combiflash to yield phenylmethyl octahydro-1(2H)-quinoxalinecarboxylate (enantiomeric mixture, cis) (2.32 g, 85%). LCMS: (M+H)+: 275.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:36]([C:35]3[CH:34]=[N:33][C:32]([Cl:31])=[CH:40][CH:39]=3)=[O:37])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)nc3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially triethylamine (0.13 ml) and 6-chloronicotinoyl chloride (107 mg, CAS 58757-38-3) and the mixture was heated at 50° C. for 4 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (177 mg, 82%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 24.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 4-aminobenzotrifluoride (1.05 g, 6.53 mmol) in 8 mL of pyridine. The crude product was recrystallized from water-DMF to yield 0.47 g of the title compound, mp 272-275° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:22]=[C:23]=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:4]([NH:22][C:23](=[O:24])[NH:2][NH2:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NN

Procedure:
20.0 Grams of hydrazine monohydrate and 200 ml of ethanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 14.8 g of octadecyl isocyanate. After completion of the addition, the temperature was returned to room temperature, followed by stirring for 1 hour, and the precipitated crystal was filtered off under reduced pressure and was recrystallized from ethanol to obtain 8.2 g of the desired product. m.p. 100° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(OCCc2ccc(C#N)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1

Procedure:
t-Butyloxycarbonylamino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (1.55 g; 4.4 mmol; from step (ii) above) was stirred in a mixture of trifluoroacetic acid (10 mL) and methylene chloride (10 mL) for 3 hours. The solvent was removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with Na2CO3/aq (sat.) and water, dried (Na2CO3) and the solvent was removed to afford a yellow oil, which crystallized upon standing. Yield: 1.19 g (100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: NCc1cccs1
Product: N#Cc1ccccc1NCc1cccs1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-aminomethylthiophene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH3:31][N:23]([C:21]1[CH:22]=[C:17]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:18]=[CH:19][C:20]=1[N+:32]([O-:34])=[O:33])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28]
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Yield: 82.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-benzyloxyphenol (5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (7.8 g).