Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C1COCC1>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: NCCOCCO
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNCCOCCO
Temperature: 0 °C
Yield: 23.3 %

Procedure:
2-(2-aminoethoxy)ethanol (11 g, 104.62 mmol, 1.00 equiv) was dissolved in THF (300 mL) and cooled to 0° C. To the stirring solution was added dropwise tert-butyl 2-bromoacetate (20 g, 102.54 mmol, 1.00 equiv) and then triethylamine (15.5 g, 153.18 mmol, 1.50 equiv) dropwise The solution was then stirred for 16 h at room temperature. The solvent was removed and the residue then dissolved in DCM and washed twice with brine, then dried over anhydrous sodium sulfate and solvent removed. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) as eluent. This resulted in 5.25 g (16%) of the product as a yellow oil. MS (ES, m/z) 220 [M+H]+
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[S:7](=[O:11])(=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=[CH:23][CH:24]=1.O1CCOCC1>CO.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH:13]1([CH2:12][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([C:20]4[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:3][C:4]=3[N:8]([CH3:9])[S:7]2(=[O:11])=[O:10])[CH2:15][CH2:14]1
Reactant: CN1c2cc(Br)ccc2N(CC2CC2)S1(=O)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccnc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-4) (0.043 g, 0.14 mmol), palladium bis(tri-tert-butylphosphine) (0.014 g, 0.027 mmol), 3-methyl-2-(tributylstannyl)pyridine (0.078 g, 0.20 mmol) and finally dioxane (1 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-(cyclopropylmethyl)-3-methyl-5-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (3-1) as a tan solid. HRMS (M+H)+: observed=330.1270, calculated=330.1271.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20](=O)([O:22]C(C)(C)C)[NH2:21]>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]3[C:20](=[O:22])[NH:21][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:11]3=[N:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CN=C(c3ccccc3)NC2)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C2=NCC(c3ccc(Cl)cc3)CN12
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 5-(4-chlorophenyl)-2-phenyl-1,4,5,6-tetrahydropyrimidine (12.9 mg, 0.048 mmol), tert-butyl carbamate (16.7 mg, 0.143 mmol) and copper(II) acetate (8.7 mg, 0.048 mmol) in 0.6 mL DMF was heated at 100° C. in a sealed reaction vessel under an oxygen gas atmosphere. After 1 hour the DMF solvent was evaporated and the residue chromatographed eluting with 5% MeOH/CHCl3 to give the title compound as a pale yellow solid (1.8 mg, 12%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.36-7.49 (m, 5H), 7.05-7.13 (m, 2H), 4.32-4.41 (m, 1H), 3.79-3.89 (m, 1H), 3.54-3.71 (m, 2H), 3.05-3.20 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:14])=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)cc(N)c1C
Solvent: CC#N
Product: COC(=O)c1c(C)c(N)cc(F)c1Br
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of methyl 3-amino-5-fluoro-2-methylbenzoate (1.37 g, 7.48 mmol) in acetonitrile (57 mL) was added N-bromosuccinimide (1.01 g, 5.66 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (1.33 g, yield 68%).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.C(O[CH2:14][N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:15]1[CH2:16][CH:6]2[CH:5]([CH2:4][CH2:3][CH:2]([CH3:1])[C:7]2=[O:8])[CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1CCC=CC1=O
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Reaction time: 3 h

Procedure:
To a solution of 1 g of 6-methyl-cyclohex-2-enone in 15 cm3 of dichloromethane are added, at room temperature, 3 drops of trifluoroacetic acid, followed by 3.6 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is brought to reflux, with stirring, for 3 hours. After cooling, potassium carbonate is added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (3aRS,5RS,7aSR)-2benzyl-5-methyl-4-perhydroisoindolone is obtained in the form of a colourless oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10](I)[CH:9]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[Cl:17][C:18]1[CH:23]=[C:22]([C:10]2[CH:9]=[C:8]([Cl:7])[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc(Cl)cc1I
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a nitrogen purged aqueous solution of sodium carbonate (2M, 14 mL) and ethylene glycol dimethyl ether (25 mL) was added 4-chloro-2-iodoanisole (2.50 g, 0.00931 mol), 2-chloropyridine-4-boronic acid (1.61 g, 0.0102 mol) and bis(triphenylphosphine)palladium (II) dichloride (327 mg, 0.00047 mol). The reaction mixture was warmed to 50° C. and stirred for 5 hours. Following LCMS analysis the reaction was warmed to 75° C. and stirred for 5 hours before cooling to room temperature. The reaction was partitioned between ethyl acetate (100 mL) and a 10% w/v aqueous solution of citric acid (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude product as an orange oil (2.95 g). The material was purified using an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as an off white solid (1.10 g).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Reactant: C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(N3CCCCC3)cc(C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80° C. overnight. The mixture was cooled to room temperature, poured into 1N HCl (1 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography (1:1 EtOAc:Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+: 465.5.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15]([NH:3][CH2:1][CH3:2])=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1
Reactant: CCN
Reactant: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCNc1ncccc1C(=O)N(C)c1ccc(OC)nc1Br
Temperature: 150 °C
Yield: 77.1 %

Procedure:
Ethylamine (0.7 g) was added to a solution of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-N-methyl-3-pyridinecarboxamide (1.9 g) in xylene (5 ml), and the resulting mixture was sealed in a pressure bottle and heated at 150° C. for 4 hours. The solution was diluted with ethyl acetate, washed with water, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:4) to give 1.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11].N1C=CC=CC=1>ClCCl>[CH2:1]([N:3]([CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11])[CH2:4][CH3:5])[CH3:2]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCl)C(=O)SC4C)ccc32)cc1OC
Reactant: CCNCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.5 g of diethylamine dissolved in 30 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3-[2-chloroethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 9 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1.C(N(CC)CC)C.[C:35](S(O)(=O)=O)([NH2:37])=[NH:36]>CN(C=O)C>[OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:37][C:35](=[NH:36])[N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1
Reactant: N=C(N)S(=O)(=O)O
Reactant: O=C(NC[C@@H]1CCCNC1)c1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)N1CCC[C@@H](CNC(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Bc) 19.3 g of the mandelic acid salt obtained under Bb) are suspended in 193 ml of DMF, treated with 21.7 ml of triethylamine and 7.75 g of formamidinesulfonic acid and stirred at room temperature. The reaction mixture is evaporated and the residue is chromatographed on RP-18 silica gel with a water-acetonitrile gradient. There are isolated 13.4 g of (S)-N-[1-(amino-imino-methyl)-piperidin-3-ylmethyl]-benzamide (R)-hydroxy-phenyl-acetate (1:1), MS (FAB): 218 M-(H2N--CN).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:4]1[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=3[CH:16]=[C:2]([Cl:1])[CH:3]=1)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3nc(-c4ccccc4)oc13)C2
Yield: 49 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamide was prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 49% yield as a white solid: mp 199-201° C.; 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, J=7.5, 2.1 Hz, 2H), 8.05 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.66-7.55 (m, 3H), 6.84 (d, J=7.8 Hz, 1H), 4.65-4.56 (m, 1H), 3.15 (d, J=10.5 Hz, 2H), 2.71-2.60 (m, 2H), 2.53 (s, 3H), 2.17-2.10 (m, 1H), 2.03 (d, J=6.6 Hz, 3H), 1.78 (br s, 1H), 1.60-1.52 (m, 1H), 1.41 (t, J=10.8 Hz, 2H), 1.16-1.10 (m, 2H); MS (ESI) m/z 410 [M+H]+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(Cl)cc1

Procedure:
2-[(4-chlorobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (14.3 g, 95 mmol). and 4-chlorobenzyl chloride (10.2 g, 63 mmol). Yield 12.1 g, (84%); yellow oil; MS: 230 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46 g) as a pale yellow oil. This was employed for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([OH:15])=O)=[CH:5][N:4]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C.ClCl>[C:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([Cl:19])=[O:15])=[CH:5][N:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: ClCl
Solvent: CN(C)C=O
Product: N#Cc1ncc(C(=O)Cl)c(C(F)(F)F)n1
Yield: 83.1 %

Procedure:
A solution of 2-cyano-4-trifluoromethylpyrimidine-5-carboxylic acid (2.0 g, 9.2 mmol), oxalyl chloride (1.4 g, 11 mmol) and DMF (4 drops) in CH2 Cl2 (46 mL) was stirred at room temperature under N2 for 0.75 h. The reaction was concentrated and distilled (b.p. 100° C., 1.5 mm/Hg) to give the title compound (1.8 g, 82% yield); 1HNMR (CDCl3) δ 9.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu](C#N)[C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]C#N
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.55 g, 5.0 mmol) in N,N-dimethylformamide (12.5 mL) was treated with copper cyanide (672 mg, 7.5 mmol). This mixture was heated at reflux for 21 h. The reaction mixture was cooled to 25° C. and poured into aqueous ammonium hydroxide (25 mL). The resulting solution was diluted with water (25 mL). This solution was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate and magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.17 g, 91.3%) as a clear oil; EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: [C:1]1([C:17]([O:19][CH3:20])=[O:18])[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:28])C(=O)C1>C(#N)C.C(Cl)Cl>[Br:28][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][C:5]2=[C:1]([C:17]([O:19][CH3:20])=[O:18])[N:2]=1
Reactant: COC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
The Intermediate 1G (3.20 g, 11.38 mmol) was dissolved in acetonitrile and NBS (2.43 g, 13.65 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. The solid was dissolved in DCM and passed through a silica gel plug, eluting with 10% methanol in DCM to give product Intermediate 1H as a yellow solid (3.90 g, 95%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:16].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C#N)c1cccc(Br)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(N)=O)c1cccc(Br)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (Example 367, Step 1) (200 mg, 0.89 mmol) in dimethylsulfoxide (4 mL) was added hydrogen peroxide (0.42 mL, 4.8 mmol) and potassium carbonate (1.23 g, 8.89 mmol). The reaction was then stirred overnight at 70° C. The resulting slurry was cooled to ambient temperature, filtered and directly purified by reverse phase HPLC (10-100% acteonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:21]1([NH:20][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a stirred solution of N-BOC-L-phenylalanine (20 g, 75.4 mmol) in methylene chloride (200 mL) is added aniline (7.0 mL, 75.4 mmol), dicyclohexylcarbodiimide (15.5 g, 75.4 mmol), and 1-hydroxy-7-azabenzotriazole (10.3 g, 75.4 mmol). The mixture is stirred at room temperature overnight. The solid is filtered away and the filtrate is washed with 5% citric acid (50 mL), a saturated solution of sodium bicarbonate (50 mL), and brine (50 mL). The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a light brown solid. The solid is recrystalized from ethyl acetate to afford N-BOC-L-phenylalanine-N-phenylamide as a white solid (11 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[CH:6]=1.[Br-].[CH3:9][C:10]1[N:15]=[C:14]([Zn+])[CH:13]=[CH:12][CH:11]=1.C1COCC1>CCOCC.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>[Cl:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=2)[S:3][CH:4]=1
Reactant: Cc1cccc([Zn+])n1
Reactant: Clc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(Cl)cs2)n1
Temperature: 40 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén Chemica Scripta, 1971, 1, 33) (1.50 g, 7.60 mmol) and 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (23.00 mL, 11.39 mmol) is added Pd(PPh3)4 (0.18 g, 0.15 mmol). The solution is heated at 40° C. overnight, diluted with Et2O (50 mL), washed with sat. NH4Cl (40 mL), dried over MgSO4, filtered on concentrated. The residue is purified by ISCO column chromatography (5%-20% EtOAc/hexane gradient) furnish the title compound (0.45 g, 2.15 mmol, 28%). 1H NMR (CDCl3), δ 2.56 (s, 3H), 7.02 (d, 7.7 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.9, 7.7, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10]([NH:23][C:20]1[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][N:21]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1

Procedure:
C6a was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid C4c and 5-methylpyrazine-2-amine (CAS 5521-58-4).