Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10].[C:18](OCC)(=[O:20])C>>[Cl:8][C:4]1[C:3]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:18](=[O:20])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Nc1cccc(Cl)c1C(O)c1ccc(F)cc1
Product: O=C1Nc2cccc(Cl)c2C(c2ccc(F)cc2)O1
Yield: 45 %

Procedure:
This compound was prepared using General Method 2 (EXAMPLE 1) from (±)-1-(2-amino-6-chlorophenyl)-(4-fluorophenyl)methanol (0.28 g, 1.1 mmol) to afford 0.14 g (45%) of (±)-5-chloro-4-(4-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]1[C:15](=O)[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11]1.[OH-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25]>C(C(C)=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]1[CH2:15][N:14]([CH2:27][CH2:26][N:24]([CH3:25])[CH3:23])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11]1
Reactant: O=C1Nc2ccccc2SC1=Cc1ccc(Cl)cc1Cl
Reactant: CN(C)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CN(C)CCN1CC(=Cc2ccc(Cl)cc2Cl)Sc2ccccc21
Product: Cl
Temperature: 25 °C

Procedure:
2-(2,4-Dichlorophenylmethylidene)-2H-1,4-benzothiazine-3(4H)-one (3.0 g) in methyl ethyl ketone (10 ml) was treated with sodium hydroxide (0.98 g) at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and added with dimethylaminoethyl chloride (1.7 g), refluxed for 3 hours and cooled to 30° C. The organic layer was washed with 20 ml of water two times, dried and evaporated under reduced pressure. The residue was dissolved in 20 ml of isopropyl alcohol and added with 0.9 ml of conc. HCl. The resulted precipitates were filtered and recrystallized from 30 ml of isopropyl alcohol to give 2-(2,4-Dichlorophenylmethylidene)-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazine hydrochloride as yellow crystals. m.p. 238° to 242° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=S)[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([NH:21][NH2:22])(=[O:20])[CH3:19].O>C(O)C>[C:18]([NH:21][NH:22][C:11]1[CH2:12][N:13]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:17]=[CH:16][S:15][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: S=C1CN=C(c2ccccc2)c2ccsc2N1
Reactant: CC(=O)NN
Solvent: O
Solvent: CCO
Product: CC(=O)NNC1=Nc2sccc2C(c2ccccc2)=NC1

Procedure:
1.5 g (0.00582 mol) of 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione are heated to reflux for 4 hours under a nitrogen atmosphere with 1.3 g (0.0175 mol) of acetyl hydrazine in 120 ml of absolute ethanol. The solvent is evaporated and the crystals obtained are shaken with water in a separating funnel. After filtration under a vacuum, the product is recrystallized from ethyl acetate containing active carbon to give colorless crystals of 2-(2-acetylhydrazino)-5-phenyl-3H-thieno[2,3-e]-1,4-diazepine, melting point 194°-196° C. (transition).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 20 h
Yield: 68.4 %

Procedure:
To a solution of methyl 3-amino-5-chloro-2-methylbenzoate (100 mg, 0.50 mmol) in 1,2-dichloroethane (2.5 ml) at room temperature and under nitrogen was added tert-butyl 4-oxopiperidine-1-carboxylate (200 mg, 1.0 mmol) followed by acetic acid (0.17 ml, 3.0 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.32 g, 1.5 mmol) at room temperature. The resulting mixture was stirred for 20 hours under nitrogen. Deionized water (5 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 131 mg (68%) of the title compound as a white solid. LC-MS 98%, m/z=405.4/406.9 (M+Na), 1H NMR (500 MHz, Chloroform-d) δ ppm 7.10 (1H, d, J=2.05 Hz), 6.70 (1H, d, J=1.89 Hz), 3.98-4.16 (2H, m), 3.88 (3H, s), 3.58-3.72 (1H, m), 3.37-3.52 (1H, m), 2.97 (2H, br. t, J=11.50, 11.50 Hz), 2.24 (3H, s), 2.06 (2H, br. d, J=10.60 Hz), 1.44-1.51 (9H, m), 1.32-1.44 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:25]([F:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[C:25]([F:33])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4F)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-2-fluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2,2′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 3%): m/z (ES+) 417 [MH+].
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C.C([O:34][CH2:35][C@@H:36]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])(=O)C(C)(C)C>>[C:56]([O:55][C@@H:36]([C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])[CH2:35][OH:34])([CH3:59])([CH3:58])[CH3:57]
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
Compound 4I was prepared following the procedure used to prepare compound 1K of Example 1, except that (S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethyl pivalate (4H) was used instead of compound 1J. LCMS-ESI+ (m/z): 370.2, 372.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[CH:6][N:5]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C#N)c(N)n2)CC1

Procedure:
A mixture of 4-amino-2-chloro-pyrimidine-5-carbonitrile (2.0 g, 12.94 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 15.53 mmol, 1.2 equiv; commercially available) in anhydrous DMF (20 mL) was heated to 60° C. for 4 h. The organic phase was concentrated under reduced pressure and the crude product purified by crystallization from ethyl acetate providing 3.02 g (74%) of the title compound. MS (ISN): 317.1 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[3H][3H]>C(OCC)(=O)C.[Rh]>[CH:10]1([CH:8]([OH:9])[CH:5]2[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Rh]
Agent: [3H][3H]
Solvent: CCOC(C)=O
Product: OC1CCC(C(O)C2CCCCC2)CC1
Yield: 84 %

Procedure:
1 g of (4-hydroxyphenyl)phenylmethanone are dissolved in 50 ml of ethyl acetate. 1 g of 5% Rh/C catalyst (50% of water) is subsequently added. The hydrogenation is carried out using hydrogen 3.0 at 40° C. and a pressure of 2 bar. When the hydrogenation is complete, the catalyst is separated off by filtration, and the solution is evaporated in a rotary evaporator, giving 900 mg of product (cis and trans isomer mixture).
Reaction SMILES: [N:1]1([C:5]2[C:10]([F:11])=[C:9]([NH:12][NH2:13])[N:8]=[C:7]([CH2:14][CH3:15])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:36]=[O:37])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[N:1]1([C:5]2[N:6]=[C:7]([CH2:14][CH3:15])[N:8]=[C:9]([NH:12][NH:13][C:23](=[O:24])[C@H:22]([CH2:21][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:26][N:27]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:36]=[O:37])[C:10]=2[F:11])[CH2:2][CH2:3][CH2:4]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CCc1nc(NN)c(F)c(N2CCC2)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
4-(1-Azetidinyl)-2-ethyl-5-fluoro-6-hydrazinopyrimidine (88 mg, 0.42 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (140 mg, 0.46 mmol), and HOAt (56 mg, 0.42 mmol) were dissolved in 3 mL of DMF. Then, NMM (71 μL, 0.65 mmol) was added, followed by EDC (75 mg, 0.40 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-{2-[6-(1-azetidinyl)-2-ethyl-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (160 mg, 76%). LCMS: (M+H)+: 499.4.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][O:23][C:22]3=[O:31])[CH2:17][CH2:16]2)=[C:11]([Cl:32])[CH:10]=1.N1C=CC=CC=1>C(#N)C>[Cl:32][C:11]1[CH:10]=[C:9]([NH:8][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reaction time: 8 h

Procedure:
Isopropylsulphonyl chloride (0.03 ml) was added to a stirred solution of the product from example 120 step (ii) (0.05 g), pyridine (0.1 ml) in acetonitrile (0.9 ml) at room temperature. The mixture was stirred overnight, partitioned between ethyl acetate and water, the organics separated, washed with water, dried, and evaporated under reduced pressure. Purification was by chromatography eluting with 40% ethyl acetate/isohexane. Yield 0.015 g.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.ClCC[I:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:34])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: ClCCI
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
A suspension of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (2.95 g, 11.7 mmol) and TMEDA (2.6 mL, 2.03 g, 17.5 mmol) in THF (80 mL) was cooled to −78° C. before the drop wise addition of n-BuLi (9.8 mL, 24.5 mmol, 2.5 M solution in hexanes). The resulting mixture was warmed to −40° C. and stirred for 40 mins. The mixture was cooled back to −78° C. before the addition of 1-chloro-2-iodoethane (3.7 mL, 7.8 g, 40.8 mmol). The resulting mixture was allowed to warm to r.t. over 2 h then quenched with NH4Cl and extracted with EtOAc (×4). The combined organics were dried (Na2SO4) and concentrated in vacuo affording 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine as a yellow solid (4.02 g, 91%). LCMS (method H): RT 4.09 min [M+H]+ 379.9
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1([CH2:12][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29](=[S:31])N)[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.S>C(O)C>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:29]([C:26]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:13]([CH3:14])[CH2:12][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:28]=2[CH:27]=1)=[S:31]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
3-Methylbutylamine (12.9 cc) is added to a solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, D series (4.1 g) in ethanol (61.5 cc), and the mixture is then saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 105° C. After being cooled, the solution is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. A yellow oil is obtained, which is purified by chromatography on a column (height: 30 cc; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (95:5 by volume) (1.5 liters) of methylene chloride and methanol and collecting 80-cc fractions. Fractions 14 to 17 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[1-(1-pyrrolidinyl)-2-propyl]-2phenothiazinecarbothioamide, D series (4.7 g) is obtained in the form of an orange oil.
Reaction SMILES: [O:1]([C:8]1[CH:19]=[C:18]2[C:11]([NH:12][CH:13]=[C:14]2[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.ClCCl.O>[O:1]([C:8]1[CH:19]=[C:18]2[C:11](=[CH:10][CH:9]=1)[NH:12][CH:13]=[C:14]2[CH2:15][CH2:16][NH:17][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(Oc3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: c1ccc(Oc2cccc(CNCCc3c[nH]c4ccc(Oc5ccccc5)cc34)c2)cc1

Procedure:
Combine 5-phenoxytryptamine (0.400 g, 1.59 mmol), 3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieves 4 Å (0.40 g) in methanol (15 mL) and stir for 4 h. Filter and wash the molecular sieves several times with MeOH. Add NaBH4 (61.5 mg, 1.59 mmol) in portions to the filtrate and stir at room temperature for 1 h. Remove the MeOH under vacuum to give a residue, dilute the residue with dichloromethane/water, separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, and dry over Na2SO4. Concentrate in vacuo and chromatograph on silica gel eluting with dichloromethane/MeOH the title compound. Form the oxalate salt of the title compound: m.p. 196-198° C.; 1H NMR (300 MHz, DMSO-d6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06 (br, 1H); MS (ELECTROSPRAY) m/e: 435.3 (M+1); HRMS (ES+) calcd for C29H27N2O2 (M+H) 435.2084 found 435.2073.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (4.0 g) synthesized in Example 265-1 and 1-bromo-4-(bromomethyl)benzene (2.94 g) were dissolved in N,N-dimethylformamide (40 mL), potassium tert-butoxide (1.32 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (4.65 g) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH:32](=[O:34])[CH3:33]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:32]([OH:34])[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC=O
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(C)O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 1.6 mL of 1.0 M n-butyllithium solution in hexanes. The resulting mixture was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 540 mg (2.0 mmol) of ethyl 2-(1-tert-butoxycarbonyl-piperidin-4-yl)acetate (from Piperidine 35, Step A) in 2 mL of THF was added and the resulting solution was stirred cold for 30 min. Acetaldehyde (0.17 mL, 3.0 mmol) was added and the resulting mixture was warmed to 0° C. The reaction was quenched with 10 mL of sat'd NH4Cl and the resulting mixture was partitioned between 50 mL of ether and 25 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromatography on 20 g of silica gel using 2:1 v/v hexanes/EtOAc as the eluant afforded the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20](CC(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(OCC)C.CO>[ClH:31].[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(C2CC(c3csc(N4CCNCC4)n3)=NO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazineacetate (i.e. the product of Example 7, Step D) (0.7 g, 1.686 mmol) in diethyl ether (10 mL) was added a 2 M solution of hydrogen chloride in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h. The resulting white precipitate was filtered and dried to give 500 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(OCC)C.O>O1CCCC1>[CH3:1][C:2]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(C(=O)O)cccc1-n1cccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1c(CO)cccc1-n1cccc1
Yield: 98.2 %

Procedure:
To a stirred solution of 7.5 grams (0.037 mole) of 2-methyl-3-(pyrrol-1-yl)benzoic acid in 125 ml of tetrahydrofuran was added dropwise 4.8 grams (0.056 mole) of a borane-tetrahydrofuran complex. The addition required 30 minutes. Upon complete addition the reaction mixture was heated under reflux for 2.5 hours then cooled slowly. To the cooled reaction mixture was carefully added 150 ml of diethyl ether previously saturated with water, followed by 50 ml of water. The mixture was poured into a separatory funnel and washed with 100 ml of aqueous 2 N sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 6.8 grams of 2-methyl-3-(pyrrol-1-yl)phenylmethanol as an oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisopropylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[CH2:17][NH:16][CH2:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:9]=3[CH2:17]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccnc1Cl
Reactant: c1ccc(Nc2ncnc3c2CNCC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Clc1cccnc1N1CCc2ncnc(Nc3ccccc3)c2C1
Temperature: 150 °C
Yield: 25.6 %

Procedure:
5,6,7,8-Tetrahydro-N-phenylpyrido[4,3-d]pyrimidin-4-amine (500 mg, 2.2 mmol) was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (423 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (190 mg).