Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
Five grams of 4-(4'-hydroxyphenyl)benzoic acid, 5 g of (s)-2-methylbutylalcohol and 11 g of p-toluenesulfonic acid were dissolved with 50 ml of benzene. Occurred water in the mixture was removed by azotropic dehydration with refluxing for eight hours. After adding 50 ml of water to the residue, the organic phase was concentrated to obtain 4-(4'-hydroxyphenyl)benzoic acid-2-methylbutyl ester (BJ).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH3:30])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH3:30])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CNC(CN1CCCC1)c1ccc(Br)cc1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (4.7 g, 17 mmol) was dissolved in 150 mL of methylene chloride and treated with N-(3,4-dichlorophenyl)-N-methylglycine (4.02 g, 16.6 mmol), EDC (3.5 g, 18 mmol), HOBt (2.47 g, 18.2 mmol), and triethylamine (2.55 mL, 18.3 mmol). The reaction mixture was stirred at room temperature for 18 h. Methylene chloride (50 mL) was added and the reaction mixture was washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 15 mL of DMSO and purified by preparative HPLC (Phenomenex 75×30 mm column, 15 injections, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 4.01 g (48%) of the title compound as a light yellow solid. MS (ES) m/e 500 [M+H]+.
Reaction SMILES: [P:1](Cl)(Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][Cl:6].[NH3:10].[NH4+:11].[Cl-]>C(Cl)Cl>[P:1]([NH2:11])([NH2:10])(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][Cl:6]
Reactant: O=P(Cl)(Cl)OCCCCl
Reactant: N
Reactant: [NH4+]
Agent: [Cl-]
Solvent: ClCCl
Product: NP(N)(=O)OCCCCl

Procedure:
A solution of 19.1 g of (0.09 mol) 3-chloropropyl phosphorodichloridate in 25 mL of CH2Cl2 was added to a solution of 10 g of (0.59 mol) NH3 in 150 mL of CH2Cl2 at -15° to -30° C. After the addition, the mixture was allowed to warm slowly to room temperature, while the excess NH3 vented. Filtering gave 24.9 g of crude material consisting of the desired product and NH4Cl (theoretical yield 25.2 g). Pure 3-chloropropyl phosphorodiamidate was obtained by extraction with methylene chloride. The 3-chloropropyl phosphorodiamidate product after drying over P2O5 had mp 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)(=O)[CH3:13]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH:12]([NH:11][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10])[CH3:13]
Reactant: COc1cccc(C(C)N)c1
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COc1cccc(C(C)NC(C)c2ccc3ccccc3c2)c1

Procedure:
In a similar fashion equal molar amounts 1-(3-methoxyphenyl)ethylamine (1.51 g, 10 mmol), 2′-acetonaphthone (1.70 g, 10 mmol) and 1.25 equivalents of titanium(IV) isopropoxide (3.55 g, 12.5 mmol) were treated as above. Work-up yielded N-[1-(2-naphthyl)ethyl]-1-(3-methoxyphenyl)ethylamine, 6F, as a clear, colorless oil; m/z (rel. int.) 305 (M+, 1), 290 (35), 170 (49), 155 (100), 135 (55), 115 (8), 105 (10), 91 (9), 77 (10).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCCBr
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
2.67 g of 4-diphenylmethoxypiperidine was dissolved in 20 ml of N,N-dimethylformamide; 1.09 ml of 3-bromopropanol and 1.66 g of potassium carbonate were added, followed by stirring at room temperature for 40 hours. After ice water was poured, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 2.32 g of the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12.C1C=C[C:15]2[N:20]([OH:21])N=NC=2C=1.[CH3:22]CN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][N:20]([CH3:15])[C:6]([C:5]1[S:1][CH:2]2[CH:11]=[CH:10][S:9][CH:3]2[CH:4]=1)=[O:7]
Reactant: O=C(O)C1=CC2SC=CC2S1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1=CC2SC=CC2S1
Reaction time: 5 h
Yield: 79.5 %

Procedure:
3a,6a-Dihydro-thieno[3,2-b]thiophene-2-carboxylic acid (2 g, 10.86 mmol) MeNHOMe—HCl (1.06 g, 10.86 mmol), HOBt (1.47 g, 10.86 mmol) and DIPEA (5.9 mL, 33.67 mmol) were combined in DMF (40 mL). To the stirred mixture was added EDCI (2.72 g, 14.12 mmol). After 5 h, EtOAc (100 mL) was added and the organics were washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 45% EtOAc/Hex) to afford the title compound (1.98 g, 80%).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH3:16][N:17]([CH3:19])[NH2:18]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[CH:6][CH:5]=[C:4]2[NH:1][C:2]([NH:18][N:17]([CH3:19])[CH3:16])=[O:3])=[CH:9][CH:10]=1
Reactant: COc1ccc2cccc(N=C=O)c2c1
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(NC(=O)NN(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude title compound of Step C (5.8 g) in toluene (85 mL) was cooled to 0° C. under N2. While stirring the reaction solution, 1,1-dimethylhydrazine (2.5 mL) was added and the mixture was allowed to warm to room temperature. After stirring for 30 min at room temperature, a precipitate formed. Filtration afforded 5.1 g of the title compound of Step D as a white solid melting at 152-153° C. 1H NMR (CDCl3): δ 8.48 (br s,1H), 7.89 (d,1H), 7.77 (m,1H), 7.58 (d,1H), 7.34 (t,1H), 7.17 (m,2H), 5.72 (br s,1H), 3.93 (s,3H), 2.72 (s,6H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the methods of Examples 75-85, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 367.2263.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42](COS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:42]2[C:43](=[O:44])[N:38]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)[CH:41]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a pale brown oil (yield: 98.9%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.[N:26]1[CH:31]=CC=CC=1.C(Cl)(Cl)=[O:33]>C1C=CC=CC=1>[C:31]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2)(=[O:33])[NH2:26]
Reactant: O=C(Cl)Cl
Reactant: c1ccncc1
Reactant: CCOC(=S)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: c1ccccc1
Product: CCOC(=S)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OC(N)=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 500 mgs of ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate in 10 ml of benzene cooled in an ice bath was added 0.1 ml of pyridine and 6 ml of a 12.5% solution of phosgene in benzene. The solution was stirred at 25° C. overnight, the precipitate filtered off and solvent removed from the filtrate under reduced pressure. The residue was dissolved in 5 ml of tetrahydrofuran and to this solution was added dropwise a solution of ammonia in tetrahydrofuran until the reaction was complete. The mixture was poured into water and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and evaporated to an oil which was chromatographed on silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane. The purified product was stirred with a mixture of ether and hexane and filtered giving ethyl (E)-6-(1,3-dihydro-4-carbamoyl oxy-6-methoxy-7-methyl-3-oxo-5-iso benzofuranyl)-4-methyl-4-thiohexenoate, mp 145°-147° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O.C1CCCCC=1.C([OH:37])C>[Pd]>[C:24]([OH:37])(=[O:23])[CH3:27].[CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:21][CH:22]=1)[NH2:5]
Reactant: CCO
Reactant: CNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(=O)O
Product: CNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1

Procedure:
N-Benzyloxycarbonyl-O-tertiarybutyl-L-tyrosine N-methylamide (2.4 g 6.2 mM) in ethanol (10 ml) was heated under reflux with cyclo hexene (4 ml) acetic acid (0.38 g 6.2 mM) and palladium on carbon (10%, 1 g) under an atmosphere of argon for 20 m. The solvents were then removed in vacuo to afford O-tertiarybutyl-L-tyrosine N-methylamide acetate m.p. 121°-123° C. This was dissolved in dichloromethane (50 ml) and shaken with aqueous saturated sodium hydrogen carbonate (50 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to afford O-tertiary butyl-L-tyrosine N-methyl amide as a crude gum which was used directly in the next step. N-[3-N-Benzyloxy carbonyl]amino-1-(R)-methoxycarbonylpropyl]-L-leucine hydrochloride (418 mg, 1 mM) in dichloromethane (10 ml) was treated with 1-hydroxybenzotriazole (159 mg, 1.0 mM) N-methylmorpholine (210 mg, 2 mM), O-tertiarybutyl-L-tyrosine-N-methyl amide (275 mg, 1.1 mM) and N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (200 mg, 1.04 mM) at 0° C. with continuous stirring. The reaction mixture was adjusted to pH7 with N-methylmorpholine and was allowed to warm to 20° C. over 16 h. The reaction was diluted with dichloromethane and washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous 3N citric acid, dried over sodium sulphate and concentrated in vacuo to afford N-[3-N-(Benzyloxycarbonyl)amino-1-(R)-methoxy carbonypropyl]-L-leucine-O-tertiary butyl-L-tyrosine-N-methyl amide (350 mg, 0.6 mM) which crystallised from ethyl acetate/hexane as needles m.p. 66°-68° C. (Found: C,64.7; H,8.1; N,9.2. C33H48N4O7 requires: C,4.7; H,7.9; N,9.1%); δ(CDCl3) 0.88 (6H,d,J=7 Hz, (CH3)2C); 1.32 (9H,s, (CH3)3C); 1.16-2.0 (5H,m,CH2,CH2CH); 2.72 (3H,d,J=5 Hz, CH3NH); 3.02 to 3.4 (6H,m,2×CH,2×CH2); 3.66 (3H,s,CH3O); 4.58 (1H,m,NHCHCO); 5.08 (2H,s,CH2C5H6); 5.2 (1H,m,NH); 6.54 (1H,m,NH); 6.88 and 7.06 (each 2H,each d,each J=8 Hz,C6H4); 7.32 (5H,m,C6H5); 7.52 (1H,m,NH).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[NH:19][CH:18]([C:20]([OH:22])=O)[CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]2([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:28]#[N:29])[CH:12]=[CH:13][CH:14]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][CH2:40][CH2:39][CH2:38][NH:37][C:20]([CH:18]1[CH:17]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:16]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)([C:28]#[N:29])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[NH:19]1)=[O:22]
Reactant: NCCCO
Reactant: CC(C)(C)CC1C(C(=O)O)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1C(C(=O)NCCCO)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 22.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 32d (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.6 g, 8 mmol), HATU and iPr2NEt in CH2Cl2 at room temperature to give rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a yellow solid (0.12 g, 22%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[N:24]([C:27]1[C:28]([Cl:47])=[CH:29][C:30]([F:46])=[C:31]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])[CH:32]=1)=[N+]=[N-].O.[C:49](O)(=[O:51])[CH3:50]>>[CH3:50][C:49]1[O:51][C:32]2[C:31]([N:33]3[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]3=[O:45])=[C:30]([F:46])[CH:29]=[C:28]([Cl:47])[C:27]=2[N:24]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c1=O
Reactant: CC(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: Cc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere a stirred solution of 4.0 grams (28 mmole) of phosphorus pentoxide and 10 mL (47 mmole) of hexamethyldisiloxane was heated at 90° C. for 30 minutes. To this was added dropwise during a 5.0 minute period a solution of 0.80 gram (2.2 mmole) of 3-(5-azido-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 5.0 mL of acetic acid. Upon completion of the addition the reaction mixture was heated at reflux for 5.0 hours, cooled to ambient temperature, and poured into 50 mL of water. The reaction mixture was extracted with three 25 mL portions of ethyl acetate. The combined extracts were washed with 50 mL of aqueous saturated sodium bicarbonate solution and 50 mL of aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of a residual oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 3:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.40 gram of an oily white solid, 3-(2-methyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 64°-66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[C:16]([C:18]1[C:19]([CH3:28])=[C:20]([O:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1)=[O:17].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:16]([C:18]3[C:19]([CH3:28])=[C:20]([O:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=3)=[O:17])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1C
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To aluminum trichloride (6.14 g, 0.046 mol) in methylene chloride (26 mL) under an atmosphere of nitrogen was added 5-Bromo-7-azaindole (67, 1.05 g, 5.31 mmol) dissolved in methylene dichloride (20.0 mL). The reaction was stirred at room temperature for 65.0 minutes, then acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (1.25 g, 5.88 mmol) in methylene dichloride (7.0 mL) was added. The reaction was stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 84 that was used directly in the next step.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:23])[NH:17]2.[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1>CC#N>[Cl:24][C:25]1[N:30]=[C:29]([O:22][C:21]2[C:13]([F:12])=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH3:23])=[CH:15]3)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(F)c(Oc3ccnc(Cl)n3)ccc2[nH]1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
DBU (5.48 mL, 36.3 mmol) is added dropwise to a suspension of 4-fluoro-2-methyl-1H-indol-5-ol (5.00 g, 30.3 mmol) and 2,4-dichloropyrimidine (4.60 g, 30.9 mmol) in CH3CN (60 mL) at 0° C. The resulting mixture is warmed to and stirred at 23° C. for 15 h. The reaction mixture is concentrated and the residue is partitioned between 1:1 EtOAc-CH2Cl2 (300 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to provide 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:55])[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][C@@H:49]([NH:53][CH3:54])[CH:50]([CH3:52])[CH3:51])[CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:53]([C@@H:49]([CH:50]([CH3:52])[CH3:51])[CH2:48][N:44]1[CH2:45][CH2:46][CH2:47][C:42]([F:55])([F:41])[CH2:43]1)[CH3:54])=[O:7]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CN[C@H](CN1CCCC(F)(F)C1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CN1CCCC(F)(F)C1)N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
3-Chloro-4-fluorobenzoic acid (0.087 g, 0.50 mmol), TBTU (0.175 g, 0.54 mmol) and NMM (0.125 mL, 1.13 mmol) was mixed in DMF (2 mL). After 10 min at rt was (S)-1-(3,3-difluoropiperidin-1-yl)-N,3-dimethylbutan-2-amine (Compound S2) (0.1 g, 0.45 mmol) and additional DMF (1 mL) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (80 mg, 47%). HRMS (M+H)+: calculated 377.1607. found 377.1613.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH:11]1([CH2:17]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:20]([N:22]1[C@H:27]([CH3:28])[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C@@H:23]1[CH3:36])=[O:21]>>[CH3:36][C@H:23]1[CH2:24][NH:25][CH2:26][C@@H:27]([CH3:28])[N:22]1[C:20]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:21]
Reactant: OCc1cc(O)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: BrCC1CCCCC1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCC2CCCCC2)ccc1F

Procedure:
5-Cyclohexylmethoxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, cyclohexylmethyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (10.8%); HPLC (XTERRA, 50/80, 220 nm) 91.4% (6.77 min); NMR δH (400 MHz, DMSO-d6) 1.016(2H, m), 1.204(8H, m), 1.735(5H, m), 2.681(4H, m), 3.291(2H, s), 3.737(2H, d, J 6.5 Hz), 3.905(2H, m) 5.078(2H, s), 6.931(2H, m) and 7.119(1H, t, J 9.0 Hz).
Reaction SMILES: ClC1C=CC([C:8]2[C:9]([N+:33]([O-])=O)=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18](C4C=CC(Cl)=CC=4)[C:17]=3[N+]([O-])=O)[CH:11]=[CH:12][C:13]=2[Cl:14])=CC=1.CC(C)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:14][C:13]1[CH:12]=[CH:11][C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([CH:8]=1)[NH2:33]
Reactant: O=[N+]([O-])c1c(Oc2ccc(Cl)c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])ccc(Cl)c1-c1ccc(Cl)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(Cl)ccc1Oc1ccc(Cl)cc1

Procedure:
A 140 g. portion of the above nitro derivative in 1400 ml. of acetone is reduced with 560 g. of sodium hydrosulfite in 1400 ml. of water as described in Example 1, giving 5-chloro-2-(p-chlorophenoxy)aniline.