Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[CH:19][CH:18]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:28][C:26]1[S:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24][N:25]=1)=[O:12])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)O)c1
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 20 ml scintillation vial was added 5-(aminosulfonyl)-2,3-dichlorobenzoic acid (40 mg, 0.148mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (28.9 mg, 0.148 mmol). To this was added EDC (28 mg, 0.148 mmol) and HOAt (20 mg, 0.148 mmol) followed by 3 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by vacuum filtration and air dried, yielding 5-(aminosulfonyl)-2,3-dichloro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide (31 mg, 47%) as light tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=S)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1CCC([N:40]=[C:41]=[N:42]C2CCCCC2)CC1.C(N(CC)C(C)C)(C)C.N#CN>C(#N)C>[C:41]([N:42]=[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:40]
Reactant: COc1ccc(NC(=S)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=NC#N)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1OC
Yield: 32.7 %

Procedure:
To an acetonitrile solution (15 mL) of N-(3,4-dimethoxyphenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinethiocarboxamide (499 mg, 1.07 mmol) described in WO 98/14431, DCC (4397 mg, 2.13 mmol), N,N-diisopropylethylamine (Hünig base) (0.19 mL, 1.09 mmol) and cyanamide (224 mg, 5.32 mmol) were added, followed by heating under reflux in argon atmosphere for 2 days. DCC (439 mg, 2.13 mmol), Hünig base (0.19 mL, 1.09 mmol) and cyanamide (224 mg, 5.32 mmol) were further added thereto, followed by heating under reflux for 2 days. After the reaction solution was concentrated, the resulting residue was purified by silica gel column chromatography to give the target compound (167 mg, 0.35 mmol).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[O:18].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=[C:11]2[CH:17]=[O:18]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
Cesium carbonate (545 mg, 1.67 mmol) was added to a stirred room temperature of 5-bromo-1H-indole-3-carbaldehyde (125 mg, 0.56 mmol) in DMF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes. Then 2-iodopropane (0.112 mL, 1.116 mmol) was added and the solution was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (2×20 mL) and saturated sodium bicarbonate (5 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (148 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([C:14](=[O:22])[CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:12][CH:11]3[CH2:23][CH2:24][CH2:25][N:10]3[CH2:9][C:8]=2[CH:26]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([C:14](=[O:22])[CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:12][CH:11]3[CH2:23][CH2:24][CH2:25][N:10]3[CH2:9][C:8]=2[CH:26]=1
Reactant: O=C(CCN1CCCC1)N1CC2CCCN2Cc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CN1CCCC1CN2C(=O)CCN1CCCC1

Procedure:
A mixture of 5 g. of 2,3,5,10,11,11a-hexahydro-7-nitro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c][1,4]benzodiazepine, 250 ml. of ethanol and 2 g. of 10% palladium on carbon catalyst is shaken under about 3 atmospheres of hydrogen pressure in a Parr hydrogenerator until hydrogen uptake is complete. The catalyst is filtered off and the mother liquor is concentrated to obtain the 7-amino-2,3,5,10,11,11a-hexahydro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([C:14](=[CH:20][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccccc1F
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1F)C(=O)OCC
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2-Fluoroaniline (25 g, 0.23 mol) and ethyl 2-butyryl-3-ethoxyacrylate (48 g, 0.23 mol) were heated at 150° for 2 hours, then diluted with petroleum ether and left to stand overnight. Filtration and washing gave ethyl 2-butyryl-3-(2-fluorophenylamino)acrylate (37.5 g), m.p. 60°-62°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(OCC)C>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: O=C(COc1ccc(C(=O)CBr)cc1)NCc1ccccc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2-[4-(bromoacetyl)phenoxy]-N-(phenylmethyl)acetamide (1.40 g) (preparation described in EPO 052442) in acetonitrile (5 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) in acetonitrile (20 ml). After stirring overnight the liquors were decanted from the residual gum, then concentrated in vacuo. Purification by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane, gave a solid. Trituration of this solid with diethyl ether gave the title compound, 95 mg: m.p. 150°-151° C.; NMR (d6DMSO) δ8.67(1H,bt) 8.15(2H,d), 8.00(2H,d), 7.26(5H,m), 7.06(2H,d), 6.81(2H,d), 4.66(2H,s), 4.34(2H,d), 3.84(2H,s), 3.33(4H,t), 2.54(4H,t); m/e 445 (M+H)+ ; calculated for C26H28N4O3. 0.25H2O: C, 69.5; H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1.[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[C:17]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1)#[N:18]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1F
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1F
Temperature: 150 °C
Yield: 56.9 %

Procedure:
A mixture of compound 23 (300 mg, 1 mmol), CuCN (355 mg, 4 mmol) in DMF (6 mL) was heated at 150° C. under N2 overnight. The reaction mixture was cooled to room temperature and then poured into ice water. EtOAc was added and the insoluble solid was filtered off (rinsed with EtOAc). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (PE:EtOAc=4:1) to afford the title compound 24 (140 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.99 (d, 1H, J=7.2 Hz), 7.55 (d, 1H, J=10.0 Hz), 2.92 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:10](=[O:11])[N:9]=[CH:8][NH:7][C:6]=2[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32]>C1COCC1>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:7]1[C:6]2[N:12]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[C:10](=[O:11])[N:9]=[CH:8]1
Reactant: CSc1nc2[nH]cnc(=O)c2s1
Reactant: Clc1cccc(CBr)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc2c(s1)c(=O)ncn2Cc1cccc(Cl)c1Cl
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
To a suspension of 2-(methylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one (2.978 g, 14.94 mmol) in THF (200 mL) at 0° C. was added dropwise of LiHMDS (18.3 mL, 16.44 mmol). The resulting mixture was stirred at 0-5° C. for 3 hours and 1-(bromomethyl)-2,3-dichlorobenzene (3.946 g, 16.44 mmol) in THF (30 mL) was added dropwise to the reaction mixture over a period of 2 hours. The reaction mixture was allowed to warm to ambient temperature slowly and stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (2×20 cm, DCM:MeOH=30:1 elution) to give the desired product as a white solid (0.671 g, 13%). 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.50 (m, 1H), 7.26˜7.16 (m, 2H), 5.56 (s, 2H), 2.74 (s, 3H); LC-MS: 358 (MH+); IR (thin film): 3073, 2986, 1651, 1619, 1598, 1426, 1384, 1221, 1055 cm−1.
Reaction SMILES: [NH2:1][OH:2].C[O-].[Na+].[C:6]([C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=O)#[N:7].Cl>CO>[C:6]([C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:1][OH:2])=[O:16])#[N:7]
Reactant: CCOC(=O)CCCCCC(C#N)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#CC(CCCCCC(=O)NO)(c1ccccc1)c1ccccc1
Yield: 85.7 %

Procedure:
To a solution of hydroxylamine (38.5 g, 0.55 mol) in methanol (300 ml) was added a solution of 28% sodium methylate in methanol (165 ml, 0.83 mol). To the mixture was added, while stirring under ice-cooling, a solution of ethyl 7-cyano-7,7-diphenylheptanoate (18.7 g, 0.055 mol) in methanol (50 ml). The mixture was stirred for 1.5 hour. After completion of the reaction, pH of the reaction mixture was made acidic with 1N HCl. The reaction mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate--hexane to give 15.2 g of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])=[O:25]
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Reaction of the auxiliary (15) (0.155 g, 0.81 mmol) in solution in tetrahydrofuran at -78° C. with butyllithium (1.0M, 0.819 ml, 0.821 mmol) and pivaloyl chloride (0.110 ml, 0.89 mmol) for 30 minutes and then at room temperature for 3 hours with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (22) as an oil (0.128 g, 57%); νmax (CHCl3) 1687 and 1775 cm-3 ; [α]D25 (c 0.4 in CHCl3)=-60.3; (Found: C, 69.94; H, 7.84; N, 4.93. C16H21 NO3 requires C, 69.80; H, 7.69; N, 5.09%); δH (CDCl3 ; 300 MHz) 0.98 (3H, s, C(CH3)2), 1.39 (9H, s, C(CH3)3), 1.60 (3H, s, C(CH3)2), 5.11 (1H, s, CHPh), 7.14-7.37 (5H, m, ArCH; δC (125 MHz; CDCl3) 23.66 (CH3), 26.20 (CH3), 28.68 (CH3), 41.63 (C), 69.03 (CH), 81.80 (C), 126.10 (ArCH), 128.44 (ArCH), 128.85 (ArCH), 136.80 (C), 153.50 (CO), 178.00 (CO); m/z (CI+, NH3) 276 (M+ +1).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH2:45]C3C=CC=CC=3)[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4].IC1C(C)=NNC=1.IC1C=CC(CC2C=CNN=2)=CC=1>>[CH3:52][Si:2]([CH3:1])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(-c4cnn(Cc5ccccc5)c4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cc1n[nH]cc1I
Agent: Ic1ccc(Cc2cc[nH]n2)cc1
Product: Cn1cc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)cn1

Procedure:
9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-2-[1-methylpyrazol-4-yl]purine-6-ylamine (15) Compound 15 was prepared in the manner of compound 11 substituting 4-iodo-methylpyrazole for 4-iodo-benzylpyrazole to afford compound 15: 1H NMR(CDCl3) 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.14 (s, 3 H, CH3), 0.78 (s, 9H, t-bu), 0.83 (s, 9H, t-bu), 0.91 (s, 9H, t-bu), 3.8 (d, 1H), 3.90 (s, 3H, N-CH3) 4.05 (d, 1H), 4.08-4.12 (m, 1H), 4.30-4.32 (m, 1H), 4.55-4.60 (m, 1H), 5.60 (bs, 1H, D2O exchangeable), 6.00-6.05 (m, 1H), 7.99 (s, 1H), 8.05 (s, 1H), 8.15 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:12][C:10]([CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:3][CH:4]=1)=[O:11]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
A solution of 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (4.69 g, 19.1 mmole, from Preparation 28 (c)), tert-butyl acrylate (11.2 mL, 76.5 mmole), DIEA (6.7 mL, 38.5 mmole), Pd(OAc)2 (215 mg, 1 mmole), and P(o-tol)3 (583 mg, 2 mmole) in propionitrile (100 mL) was purged with Ar, then was heated at reflux. After 18 h, the reaction was allowed to cool to room temperature then was concentrated to dryness. The residue was purified by flash chromatography on silica gel (40% EtOAc/hexane) to give the title compound (5.21 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1 H), 7.62 (dd, 1 H), 7.47 (d, J=16.0 Hz, 1 H), 6.48 (d, J=8.7 Hz, 1 H), 6.17 (d, J=15.9 Hz, 1 H), 5.21 (br s, 1 H), 4.20 (d, J=5.4 Hz, 2 H), 3.79 (s, 3 H), 1.52 (s, 1 H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[OH:15]>O1CCOCC1>[CH3:19][O:18][C:13]([CH:14]([O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:16])=[O:17]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
First, 0.8 g of sodium hydride was added to a mixture of 3.17 g of 2-chloro-3-nitropyridine, 2.19 g of methyl lactate, and 20 ml of 1,4-dioxane at 10° C., and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 3.3 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])C.O>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH:9]=[O:11]
Reactant: NCCc1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNCCc1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(2-thienyl)ethylamine (15.0 g, 118 mmol) was dissolved in formic acid (120 ml) while cooling with an water bath. The solution was cooled to 0° C. Acetic acid anhydride (45 ml was added dropwise. The reaction mixture was stirred at room temperature for 3 h. It was cooled to 0° C., and water (45 ml) was added dropwise. The mixture was stirred for 16 h, while it was warming up to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The solution was washed with water (2×150 ml) and saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane (2:1) as eluent to give 14.30 g of N-(2-(2-thienyl)ethyl)formamide.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:18](C)[C:19](=O)OCC1C=CC=CC=1)[CH2:16][OH:17].[H][H]>CO.[Pd]>[OH:17][CH2:16][C@@H:15]([NH:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN[C@H](CO)CCCN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
To a solution of (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 12.65 mmol) in MeOH (100 mL) was added Pd/C (1.0 g). The mixture was transferred to an autoclave reactor, charged with hydrogen (50 psi), and stirred at RT overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindolin (3.2 g, 97%) which was used without purification. LRMS (M+H+) m/z 263.1.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:21][CH:22]([CH3:28])[CH2:23][O:24][C:25](Cl)=[O:26].O>CN(C=O)C>[CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH:15][C:25]([O:24][CH2:23][CH:22]([CH3:28])[CH3:21])=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)COC(=O)Cl
Reactant: C=CCNc1nc(N)c2cc([N+](=O)[O-])ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNc1nc(NC(=O)OCC(C)C)c2cc([N+](=O)[O-])ccc2n1
Reaction time: 3 h
Yield: 18.6 %

Procedure:
500 mg (2.04 mmol) of 2-allylamino-4-amino-6-nitroquinazoline was dissolved in 5 ml of DMF, and then 80 mg (2.33 mmol) of 70% sodium hydride and 280 mg (2.05 mmol) of 2-methylpropoxycarbonyl chloride were added thereto under ice cooling, followed by stirring for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, successive washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 131 mg (19.1%) of the title compound.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)(=[O:29])=[O:28]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:36]2[C:35]3[C:39](=[C:31]([CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH:32]=[CH:33][CH:34]=3)[NH:38][CH:37]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
95.7 mg (0.43 mmol) of indium(III) chloride and 0.04 ml (0.49 mmol) of trifluoroacetic acid were added to 83.3 mg (0.40 mmol) of the compound from Example 167A and 100 mg (0.25 mmol) of the compound from Example 86A with a purity of 53% under argon in 5 ml of dichloromethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 41.0 mg (33% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc(O)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 200 ml was added and allowed to stand for one hour. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.941 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1-(3-chlorophenyl)-2-nitro-ethanol (26 g, 0.14 mol) in DMF (50 mL) were added imidazole (28.6 g, 0.42 mol) and chlorotriethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude product was purified by flash chromatography (2% EtOAc/hexane) to yield the title compound (37 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (1H, s), 7.27–7.32 (3H, m), 5.40 (1H, dd, J=3.2, 9.5 Hz), 4.51 (1H, dd, J=9.5, 12.1 Hz), 4.36 (1H, dd, J=3.3, 12.1 Hz), 0.85 (9H, t, J=7.5 Hz), 0.54 (6H, q, J=7.5 Hz).