Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:45]=[CH:46][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1

Procedure:
0.31 g of compound 59 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.11 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH:5]1[CH3:18])(=[O:3])[CH3:2].[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COc1ccc2c(c1)C(CCBr)C(C)N2C(C)=O
Product: COc1ccc2c(c1)C(CCN1CC=C(c3ccccc3)CC1)C(C)N2C(C)=O

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)-5-methoxy-2-methylindoline with 1,2,3,6-tetrahydro-4-phenylpyridine gives white crystals, m.p. 113°-115°C., after recrystallization from dilute methanol.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[C:6]2[C:7]([CH:13]([OH:15])[CH3:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[C:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:16]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C(C)O)c2cc(C(F)(F)F)nn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c2cc(C(F)(F)F)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
The compound of Example 134 (1.64 g) was dissolved in dichloromethane (30.0 mL). To this solution, activated manganese dioxide (5.48 g) was added and the mixture was stirred at room temperature for 16 hours. Subsequently, a second portion of activated manganese dioxide (5.48 g) was added and the mixture was stirred at room temperature for 10 hours. A third portion of activated manganese dioxide (5.48 g) was then added and the mixture was stirred at room temperature for 10.5 hours. Finally, a fourth portion of activated manganese dioxide (2.74 g) was added and the mixture was stirred for 13.5 hours. Subsequently, the reaction mixture was filtered through Celite and the filtrate was evaporated to afford the title compound as a pale yellow powder (1.08 g).
Reaction SMILES: BrBr.[C:3]([O:6][C:7](Br)=[C:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.[CH3:18][OH:19]>C(Cl)(Cl)(Cl)Cl.O>[CH3:3][O:6][CH:7]([O:19][CH3:18])[CH:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CO
Reactant: CCCCCCCC(Br)=C(Br)OC(C)=O
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC(Br)C(OC)OC
Reaction time: 48 h

Procedure:
The oil is mixed with 200 ml of carbon tetrachloride and cooled in an ice bath. Bromine, diluted with an equal volume of carbon tetrachloride, is added slowly with agitation while maintaining the temperature below 10°C. Bromine addition is stopped when the bromine is no longer decolorized. To the brominated mixture, containing 1,2-dibromononen-1-yl acetate, is added 500 ml of methyl alcohol with shaking and cooling. The mixture is allowed to stand two days with occasional shaking and then diluted with 1.5 liters of water. The separated oil is washed with 5% sodium carbonate solution until free of acid and then fractionally distilled in the presence of a small amount of sodium carbonate to yield 2-bromo-nonanal dimethyl acetal.
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:13][CH:14]([NH2:23])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:13][CH:14]([NH:23][CH2:12][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)COc1ccccc1
Reactant: Oc1ccc(OCC2CO2)cc1
Product: CC(COc1ccccc1)NCC(O)COc1ccc(O)cc1

Procedure:
A mixture of 1.66 g. (10 mmole) of 4-(2,3-epoxy-1-propoxy)-phenol and 4.5 g. (30 mmole) of 1-methyl-2-phenoxyethylamine was heated at 90° C. for 3 hours. The residue was triturated with ether and filtered. Recrystallization from ethyl acetate to which a little methanol was added gave 1-(1-methyl-2-phenoxyethylamino)-3-(4-hydroxyphenoxy)-2-propanol; mp 173°-175° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:24])[C:15]=2[Cl:25])[C:7]([CH:11]=[O:12])=[C:8](I)[N:9]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(OCC)(=O)C.O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:24])[C:15]=2[Cl:25])[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A suspension of 34.2 g (0.069 mol) of methyl 4-[(2-butyl-5-formyl-4-iodo-1H -imidazol-1-yl)methyl]-2,3-dichlorobenzoate and 6.84 g of 10% palladium on carbon in 850 mL of ethyl acetate was shaken under hydrogen at 3 Torr for 1 hour. The mixture was filtered through Celite® and concentrated under vacuum to 300 mL. This solution was washed in turn with 5% sodium carbonate solution, water, and brine and then concentrated to an oil which crystallized on standing. This was dissolved in 25 mL of hot methanol which when cooled gave crystals. The suspension was slowly diluted with water and then filtered to give 24.39 g (96%) of crystals; mp 94°-96° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]=[CH:13][N:12]([C:18](=[O:19])[N:17]([CH3:21])[CH3:16])[N:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)c2nc[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2ncn(C(=O)N(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A suspension of 3-(4-toluenesulfonyl)-1H-1,2,4-triazole (100 mg), dimethylcarbamoyl chloride (62 μl) and potassium carbonate (124 mg) in N,N-dimethylformamide was stirred at room temperature for 70 minutes. To the reaction mixture were added ethyl acetate and water, and extraction was carried out with ethyl acetate. The obtained organic layer was washed three times with water, and then dried over magnesium sulfate. The residue was purified by a short-column chromatography (eluent: n-hexane/ethyl acetate=3/1) to yield a clear oil (77 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=3)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:28]1([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=3)[C:22]([C:23]#[N:24])=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][O:5][C:6]3=[O:32])=[CH:9][CH:10]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OCCCCl)cc3)n(C3CCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4CCCOC4=O)cc3)n(C3CCC3)c2c1
Temperature: 80 °C

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indole-2-yl)-phenyl]-carbamic acid 3-chloro-propyl ester in 5 mL of DMF is added anhydrous K2CO3. The resulting mixture is stirred at 80° C. until complete consumption of the starting material is determined by TLC. After cooling, 10 mL of water is added to the reaction mixture to afford a solid precipitation which is collected by filtration, followed by washing with ether. The desired 1-cyclobutyl-6-ethoxy-2-[4-(2-oxo-[1,3]oxazinan-3-yl)-phenyl]-1H-indole-3-carbonitrile is obtained as a white powder (76.2 mg, 91.8% yield).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:13]=1[CH2:14][NH:15][C:16]1[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(OC(C)(C)C)=O.C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:13]=1[CH2:14][NH:15][C:16]1[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(OCCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(OCCN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
2-[2-(N-Boc-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide (0.02 g, 0.04 mmol) was dissolved in 2 mL of a 1:3 mixture of trifluoroacetic aicd:methylene chloride. The reaction mixture was stirred at room temperature for 30 min. The solvent was removed, and the material was purified by ion exchange chromatography to afford the title compound (0.014 g, 88%) as the free base.
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ 1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30](=[O:41])[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1)([CH3:33])[CH3:32])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:40][C:36]3[CH:35]=[C:34]([C:31]([CH3:33])([CH3:32])[C:30]([OH:41])=[O:29])[CH:39]=[CH:38][CH:37]=3)=[O:26])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)C(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: CC(C)(C(=O)O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 2-(3-amino-phenyl)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-chloro-phenyl)-2-methyl-propionic acid using Mutti's procedure (S. Mutti et al. Synth. Comm. 1997, 27, 425)) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.52 (1H, br s), 7.70 (2H, m), 7.32 (1H, m), 7.12 (1H, d), 2.93 (3H, m), 1.98-1.35 (33H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 63.89; H, 8.61; N, 7.77%; C39H60N4O8.1.0 mol H2O requires: C, 64.09; H, 8.55; N, 7.67%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:21](=[O:23])[NH2:22])([CH2:15][C:16](OCC)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16](=[O:17])[NH:22][C:21]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(N)=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Reaction time: 6 h
Yield: 88.5 %

Procedure:
(R)-diethyl 2-t-butyloxycarbonylamino-2-carbamoylsuccinate (590 mg) obtained in Example 15 was dissolved in acetone (6 mL) and water (6 mL), the solution was added with potassium carbonate (295 mg), the mixture was stirred for 6 hours, 1 mol/L hydrochloric acid was poured to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (450 mg, yield: 88%) as colorless crystals. Optical rotation [α]D25 was −39.1° (c 0.50, ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@@:11]3([O:13][CH2:12]3)[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][S:19][Na]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@@:11]([CH2:12][S:19][CH3:18])([OH:13])[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1N[C@H]1CCC[C@]2(CO2)C1
Reactant: CS[Na]
Solvent: C1CCOC1
Product: CSC[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-chloro-5-fluoro-N-((3R,5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine, 49b, (0.10 g, 0.38 mmol) was dissolved in THF (2 mL). Methylsulfanylsodium (0.08 g, 1.15 mmol) was added to the reaction and the mixture was allowed to stir at room temperature for 3 hrs. An additional 36 mg portion of methylsulfanylsodium in THF (2 mL) was added and the reaction mixture was stirred overnight at room temperature. After LCMS showed starting material was still present, the reaction was warmed to 50° C. and stirred for 1 hr. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% Etoac/hexanes gradient). The product (contaminated with small amount of staring material) was carried on to the next step without further purification. LCMS RT=3.56 (M+1) 306.2.
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=2[C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[O:4]C1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:17][O:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]([CH:5]=[O:4])=[C:9]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[CH:10]=1
Reactant: COc1cc(-c2noc(C)n2)c(C2OCC(C)(C)CO2)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C=O)c(-c2noc(C)n2)cc1OC

Procedure:
g of 3-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4,5-dimethoxy-phenyl]-5-methyl-[1,2,4]-oxadiazole were stirred in 100 ml of acetone in the presence of 10 ml of concentrated HCl for 3 hrs. at room temperature. Then, the pH of the reaction mixture was adjusted to 7 with saturated NaHCO3 solution, the acetone was removed in a vacuum and the mixture was extracted with ethyl acetate. After removal of the solvent the residue was purified by column chromatography (CH2Cl2/ethyl acetate) and there were obtained 1.12 g of 4,5-dimethoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzaldehyde as a white solid; MS: 248 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[N:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl>CN1CCCC1=O.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[N:26]4[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Clc1ccc(Sc2ccc([C@@H]3CC[C@@H]4CCCCN43)cc2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 4.1 g (0.028 mole) of 4-chlorothiophenol in 40 mL of dry N-methylpyrrolidinone was added to 0.028 mole of sodium hydride (from 1.36 g of 50% sodium hydride washed free of oil with hexane) under an atmosphere of nitrogen. Then a solution of 5.3 (0.019 mole) of trans-3-(4-bromophenyl)octahydroindolizine in 50 mL of dry N-methylpyrrolidinone and 1.35 g of cuprous oxide was added to the mixture and the reaction mixture was refluxed overnight. Then the reaction was cooled to room temperature, MeOH was added, and the mixture was filtered. The solvent was evaporated in vacuo to a brown oil. The oil was flash chromatographed in SiO2 using 98% hexane, 2% acetone as the eluant. The product was collected in fractions 6 and 7, and evaporation of the solvent in vacuo gave an oil. The oil was treated with ethereal HCl to give a solid salt. The solid was recrystallized from acetonitrile to give 77 g (10% yield) of the title compound as a white solid, mp=198°-201° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([Br:13])[CH:12]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Br:13][C:11]1[C:12]2[C:4](=[O:3])[NH:5][CH2:6][CH2:7][C:8]=2[S:9][CH:10]=1
Reactant: CCOC(=O)NCCc1cc(Br)cs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2scc(Br)c21
Yield: 51.6 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 4, [2-(4-bromo-thiophen-2-yl)-ethyl]-carbamic acid ethyl ester (I-15c: 6 g, 21.73 mmol) in POCl3 (60 mL) was reacted with P2O5 (6.217 g, 43.782 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 2.6 g of the product (52% yield).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].C1COCC1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>CCOC(C)=O>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (50.2 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc and Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 71% (100 mg, 0.181 mmol) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[N:19]O)[C:9]1[CH:18]=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[CH:11][CH:10]=1>CCOCC>[C:8](#[N:19])[C:9]1[CH:18]=[CH:17][C:12]([C:13]#[N+:14][O-:15])=[CH:11][CH:10]=1
Reactant: ON=C(Cl)c1ccc(C(Cl)=NO)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#[N+][O-])cc1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a 300 ml, three-necked, round bottomed flask equipped with a magnetic stirrer, a thermometer, and a 125 ml dropping funnel topped with a drying tube was added triethylamine (6.1 g, 60 mmoles) and ether (150 ml). The solution was cooled to -5°C in an ice/salt bath and a solution of terephthalhydroximoyl chloride (4.7 g, 20 mmoles) in ether (75 ml) was added dropwise at -5°C with rapid stirring over a period of 20 minutes. The resulting white suspension was stirred an additional 40 minutes at -5°C. Cold distilled water (30 ml) was then added and the suspension was stirred an additional 20 minutes at 0°to -5°C and was then filtered on a sintered glass filter. The nearly white solid was washed thoroughly on the filter with cold distilled water (3 × 25 ml) and cold ether (3 ×0 25 ml) and was then dried in a vacuum desiccator for 2 1/4hours (0.7 mm Hg) to yield 3.1 g (95%) of nearly white, fluffy terephthalonitrile oxide (TPNO). (As a word of caution, the dry material decomposed explosively when heated to 155°C in air).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14].[N+:15]([O-])([O-:17])=[O:16].[K+]>C(Cl)CCl>[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[CH3:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 91.5 %

Procedure:
Concentrated sulfuric acid (250 ml) was added to a stirred solution of 2-chloro-4-fluorotoluene (50.0 g, 0.346 mole) in ethylene dichloride (250 ml) at 0° C. Potassium nitrate (35.0 g, 0.346 mole) was then added slowly, maintaining the temperature below 10° C. The reaction was monitored by gas chromatography. Upon the disappearance of 2-chloro-4-fluorotoluene, the reaction mixture was poured into ice and extracted with methylene chloride. The dried organic layer was concentrated under reduced pressure to yield 60.0 g of 2-chloro-4-fluoro-5-nitrotoluene. This reaction was repeated several times.