Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11]C[N:9]2[C:4](=NCCC2)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:21])CC#N)([CH3:15])([CH3:14])[CH3:13].BrCCCBr>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([C:3]1([C:4]#[N:9])[CH2:2][CH2:1][CH2:11]1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(C#N)CCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DBU (23.5 mL) was added slowly to a solution of cyano-acetic acid tert-butyl ester (8.84 g) in DMF (100 mL) at rt, followed by addition of 1,3-dibromopropane (13.9 g); then the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was column purified to give title compound (6.58 g). 1H NMR in CDCl3, δ in ppm: 2.8-2.5 (m, 4H), 2.4-2.2 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.[Cu]I>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(I)c1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccccc2C(=O)O)c1
Yield: 39.6 %

Procedure:
First, 2-[(3-methoxyphenyl)thio]benzoic acid was prepared. A mixture of thiosalicylic acid (1.5 g, 9.7 mmol), 3-methoxyiodobenzene (4.6 g, 19.4 mmol), copper (I) iodide (0.07 g, 0.4 mmol), potassium carbonate (4.0 g, 29.2 mmol), and N,N-dimethylformamide (25 mL) was heated at reflux for 2 h and then cooled to ambient. The reaction mixture was diluted with ether, washed twice with 10% aqueous HCl, and dried (Na2SO4). The solvent is removed at reduced pressure to deposit a brown solid. The product was purified by recrystallization from heptane to provide 1.0 g (40% of theory) of 2-[(3-methoxyphenyl)thio]benzoic acid as a tan solid. 1H NMR (CDCl3): δ 3.80 (s, 3H), 6.90 (d, 1H), 7.00 (d, 1H), 7.25 (m, 5H), 8.11 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:34])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzyl chloroformate (22 mg, 0.131 mmol). The mixture was warmed to ambient temperature and stirred an additional 2 hours, evaporated and the residue purified by preparative reverse-phase chromatography to give trans-benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)carbamate: 1H NMR (DMSO-d6, 400 MHz) 8.13(s, 1H), 7.85(t, 1H), 7.3-7.42(m, 10H), 6.02(bs, 2H), 5.06(s, 2H), 4.54(m, 1H), 4.26(d, 2H), 1.44-2.37(m, 20H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 22.15 min.; MS:MH+ 554.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH:67]=[CH:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:64][CH:65]=[CH:66][CH2:67][CH2:68]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1=CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CC=CCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 1,2,3,6-tetrahydropyridine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5]([O:13][CH3:14])=[C:4]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[N:1]=[CH:28][NH:29][C:8]2=[O:10]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: [CH2:1]([S-:4])[CH2:2][CH3:3].[Na+].[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9](F)[CH:8]=1.O>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]([S:4][CH2:1][CH2:2][CH3:3])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: CCC[S-]
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1cc(F)cc(Br)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Dissolve sodium propanethiolate (7.5 g) in DMF (250 mL) at ambient temperature, then chill to −30° C. and add 1-bromo-3,5-difluorobenzene (8.35 mL). After 1 hour, warm to −15° C., and stir for an additional 3 hours. Pour into water (2 L) and extract into hexanes (3×500 mL). Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter and concentrate. Filter through a plug of silica gel, wash with 10:90 ethyl acetate:hexanes and concentrate to give 1-bromo-3-fluoro-5-propylsulfanylbenzene (16.2 g, 90%). The title compound is prepared essentially as described in Preparation 343.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]=[CH:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCOCCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 38.1 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.037 g, 0.050 mmol) and Rh/Al (5%) (0.021 g, 0.010 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (2R,6S,13aR, 14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.014 g, 38%). MS: Calcd.: 735. Found: [M+H]+ 736. 1H NMR (400 MHz, d6-DMSO) δ 1.08 (s, 1H), 8.79 (b, 1H), 7.34 (m, 1H), 7.10-7.20 (m, 3H), 5.28 (m, 1H), 4.66 (s, 4H), 4.41 (m, 1H), 4.20 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.42-3.47 (m, 2H), 2.97 (m, 1H), 0.79-2.38 (m, 28H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CC(C)([O-])C.[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 0.065 mol) in THF (300 mL) was added potassium tert-butoxide (9.15 g, 0.082 mol) at r.t. over 5 min. A slight exotherm was noticed and suspension was cooled with the aid of a water bath. Benzenesulfonyl chloride (10.5 mL, 0.082 mol) was then added drop-wise over a period of 10 min and the resulting suspension stirred for a further 3 h. Then water (20 mL) was added drop-wise and the solution was then stirred for 15 min. The solvent was evaporated under reduced pressure and the reaction mixture was eluted with ethyl acetate (1.2 l), washed with brine (2×100 mL), dried and concentrated. The resulting solid was triturated with ethyl acetate (50 mL) to afford 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 6.75 (1H, d), 7.55-7.625 (2H, t), 7.70 (1H, t), 7.82 (1H, d), 8.25 (1H, d) and 8.80 (1H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:2]1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:20]=2[CH2:21][CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]([CH2:37][C:38](=O)[CH3:39])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:21]([C:20]1[O:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1]/[C:38](/[CH3:39])=[CH:37]\[C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[CH3:22]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CCc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 52 and 87 mg (0.54 mmol) of benzoylacetone to yield 145 mg (51%) of example 55: TLC (DCM/MeOH, 4/1): Rf=0.60; 1H NMR (DMSO-d6, 300 MHz) δ11.42 (d, 1H, J=9.0), 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 7.48-7.32 (m, 6H), 7.11 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 5.53 (s, 1H), 4.1 (t, 1H, J=6.3), 3.2-3.14 (m, 2H), 2.86 (t, 2H, J=6.3), 2.79-2.74 (m, 1H), 2.67 (q, 2H, J=7.5), 1.65 (s, 3H), 1.17 (t, 3H, J=7.5); low resolution MS (ES+)m/e 525.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.O>CC#N>[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)CCC(N)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC(Nc2ncnc3c([N+](=O)[O-])cccc23)CC1
Yield: 69.4 %

Procedure:
To a solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) in CH3CN (3 mL) were added K2CO3 (300 mg, 2.15 mmol) and 4,4-dimethylcyclohexanamine hydrochloride (352 mg, 2.15 mmol) and the reaction mixture was heated at reflux for 3 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.58-8.55 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.38-8.35 (d, J=7.2 Hz, 1H), 8.25-8.22 (d, J=7.8 Hz, 1H), 7.67-7.61 (t, J=7.8 Hz, 1H), 4.17 (m, 1H), 1.75-1.56 (m, 4H), 1.46-1.18 (m, 4H), 0.98 (s, 3H), 0.95 (s, 3H); MS [M+H]+: 301.20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=O)[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:22])/[C:16](/[CH3:21])=[CH:17]/[CH:18]=[CH:19]\[CH3:20])=[O:5])[CH3:2].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>CCO.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH2:13][NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:8][N:7]1[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])=[O:5])[CH3:2]
Reactant: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@H](CCCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of (2S,3R)-1-((2E,4Z)—(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl)pyrrolidine-2-carboxylic acid ethyl ester (1.g, crude) in EtOH (10 mL) is added phenethylamine (0.44 g, 3.65 mmol) at r.t. After stirring at r.t. for 30 min, NaBH3CN (0.3 g, 4.87 mmol) is added in one portion, After stirring at r.t. for 1.5 Hrs, the reaction solution is diluted with 50 mL of ether and washed with 20 mL of brine. The ether layer is concentrated and the crude product is purified by chromatography (CH2Cl2/MeOH: 97/3) to give a pale liquid (405 mg, 30.0%). (NMR and MS data confirmed, U-4117-52-20).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(=O)(OC)[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14]>S(=O)(=O)(O)O>[F:13][C:10]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]([OH:6])=[C:8]([CH3:14])[CH:9]=1
Reactant: COC(=O)Oc1ccc(F)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A mixture of concentrated nitric acid (6 ml) and concentrated sulphuric acid (6 ml) was added slowly to a solution of 4-fluoro-2-methylphenyl methyl carbonate (11.34 g, 62 mmol) in concentrated sulphuric acid (6 ml) such that the temperature of the reaction mixture was kept below 50° C. The mixture was stirred for 2 hours, then ice/water was added and the precipitated product collected by filtration. The crude product was purified by chromatography on silica eluting with methylene chloride/hexane progressing through increasingly polar mixtures to methanol/methylene chloride (1/19) to give 4-fluoro-2-methyl-5-nitrophenol (2.5 g, 22%) as a solid. 1H NMR Spectrum: (DMSOd6; CD3COOD) 2.31(s, 3H), 7.38(d, 1H) ,7.58(d, 1H) MS-ESI: 171 [MH]+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[Li]CCCC.CN([CH:31]=[O:32])C.Cl>C1COCC1>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:31]=[O:32])[CH:11]=[CH:10]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25 mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere. Then the mixture was cooled down to −78° C. and a solution of n-BuLi in THF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixture dropwise. The mixture was stirred at −78° C. for 15 min. then DMF (2.4 mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at −78° C. for 1 h. When the reaction completed, 1 M HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde as a white solid (1.16 g, 60%). EDI-MS: 311.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.24 (s, 1H), 7.92-7.87 (m, 2H), 7.77 (d, 1H), 7.22-7.19 (m, 2H), 4.42-4.30 (m, 1H), 2.30-2.28 (m, 2), 1.93-1.90 (m, 2H), 1.48-1.11 (m, 5H), 0.82 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:48])=[C:42]([NH:44][C:45](=[O:47])[CH3:46])[CH:43]=1.OP(O)(O)=O>O.CO>[C:45]([NH:44][C:42]1[CH:43]=[C:38]([NH:37][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:39]=[CH:40][C:41]=1[CH3:48])(=[O:47])[CH3:46]
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)ccc1C

Procedure:
Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl)acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1H, br. s.), 9.52-9.58 (2H, m), 9.21 (1H, s), 8.94 (1H, t, J=5.52 Hz), 8.18 (1H, s), 7.87 (1H, s), 7.59-7.63 (2H, m), 7.44-7.54 (2H, m), 7.06 (1H, d, J=8.28 Hz), 6.81-6.85 (1H, m), 3.59 (3H, q, J=5.69 Hz), 3.24 (2H, q, J=5.86 Hz), 2.73-2.84 (6H, m), 2.08 (3H, s), 1.98 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH2:10][CH:11]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][CH:14]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[S:17][C:13]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][CH2:11][N:30]4[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]4)[CH:7]=[CH:6][CH:5]=3)=[CH:14][N:15]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: O=C(O)C1CNC1
Reactant: CCc1c(CCC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(CCCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-{5-[2-ethyl-3-(3-oxopropyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methyl ethyl)oxy]benzonitrile (D115) (150 mg, 0.371 mmol), 3-azetidinecarboxylic acid (75.0 mg, 0.742 mmol) and acetic acid (0.1 ml, 1.747 mmol) was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (236 mg, 1.112 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous HCl (2M). The organic phase was concentrated and purified by Mass Directed AutoPrep to afford 1-{3-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethyl phenyl]propyl}-3-azetidinecarboxylic acid (E93) (80 mg) as a TFA salt.