Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of 10% TFA/CH2Cl2 (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was dried under reduced pressure and the product was purified by RP-HPLC to provide 16 mg (80%) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15 (s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 18.09 ppm; MS (m/z) 436 [M−H]−, 438 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:25]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[CH:33][C:32]=1[C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1)(=[O:30])=[O:29])([CH3:27])[CH3:26]>>[CH3:41][N:39]([CH3:40])[C:38](=[O:42])[NH:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([CH:25]([CH3:26])[CH3:27])(=[O:30])=[O:29])=[C:32]([C@H:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:12](=[O:14])[C@H:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:1]([NH2:2])=[O:3])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:33]=1
Reactant: COc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1F
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Agent: Cl
Product: COc1cc([C@@H](Nc2cccc(C(N)=O)c2)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)ccc1F

Procedure:
Example 59 was prepared according to the general coupling condition using 7D and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (d, J=6.57 Hz, 3 H) 1.40 (d, J=6.82 Hz, 3H) 1.64-1.80 (m, 1H) 1.92-2.20 (m, 2H) 2.39-2.57 (m, 1H) 2.97 (s, 6H) 3.62-3.76 (m, 4H) 3.81-3.95 (m, 1H) 4.06-4.18 (m, 1H) 5.38 (s, 1H) 5.63 (dd, J=8.08, 5.05 Hz, 1H) 6.78-6.89 (m, 2H) 6.93-7.08 (m, 3H) 7.09-7.22 (m, 3H) 7.25 (dd, J=8.72, 2.15 Hz, 1H) 7.69 (d, J=8.84 Hz, 1H), LC-MS 640 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:33][CH:31]3[CH2:30][C:29]4[CH:35]=[C:25]([O:24][CH2:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:26]=[CH:27][C:28]=4[O:32]3)[CH2:12][CH2:13]2)=[CH:15][CH:16]=1)[CH3:2]
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: CCc1ccc(CC2(O)CCNCC2)cc1
Product: CCc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1

Procedure:
The title compound MS: m/e=458.6 (M+H+) was prepared from 4-(4-ethyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:26][C@H:27](O)[CH3:28])[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][C@H:27]([CH3:28])[CH2:26][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
To a solution of 2-(phenylmethoxy)benzoic acid (4.0 g, 17.5 mmol), (2R)-1-(tert-butyldimethylsiloxy)propan-2-ol (2.78 g, 14.6 mmol), and 4-(dimethylamino)pyridine (183 mg) in 100 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (4.2 g, 17.5 mmol) was slowly added. The resulting mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad, and concentrated under reduced pressure. Chromatography (silica gel, 1:12 ethyl acetate/hexane) of the residue afforded 1.7 g (29%) of (1R)-1-Methyl-2-(tert-butyldimethylsiloxy)ethyl 2-(phenylmethoxy)benzoate.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][C:28](=O)[CH2:29]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([CH3:34])=[CH:33][C:24]=3[CH3:23])[CH2:29]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: Cc1cc(C)c2c(c1)CC(=O)CC2
Product: CCCC(NC1CCc2c(C)cc(C)cc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 5,7-dimethyl-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 21.0, 24.3, 25.3, 25.6, 26.6, 29.7, 30.7, 36.6, 37.1, 38.0, 53.0, 53.3, 56.0, 59.1, 60.4, 60.8, 67.3, 104.7, 127.9, 28.0, 128.6, 128.7, 131.1, 131.3, 131.6, 134.6, 135.1, 135.2, 136.4, 137.3, 172.5, 172.6; MS m/z 466.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](Cl)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][C:31]([F:38])([F:37])[C:32]([CH3:36])([OH:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:35][C:32]([C:31]([F:38])([F:37])[F:30])([CH3:36])[CH2:33][CH3:34])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CCC(C)(O)C(F)(F)F
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Solvent: ClCCl
Product: CCC(C)(OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
900 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-chloro-3-oxo-1-propenyl]-cyclopropane carboxylate were dissolved in 3 ml of methylene chloride and 1 ml of 1-trifluoromethyl-1-methyl propanol was added thereto. The mixture was stirred for 16 hours at room temperature under inert atmosphere and away from humidity. After 3 days at room temperature, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 8-2 mixture of hexane-ethyl ether to obtain 570 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(1-trifluoromethyl-1-methylpropyloxy)-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]#[N:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 2-bromobenzenethiol (6.3 mL, 53 mmol), K2CO3 (13.8 g, 100 mmol) and 2-chloroacetonitrile (3.2 mL, 50 mmol) in DMF (50 mL) was stirred at 25° C. for 6 h, poured into water (700 mL), and extracted with petroleum ether (300 mL) followed by DCM (2×200 mL). The combined DCM extracts were concentrated to dryness, and re-dissolved in petroleum ether/ethyl acetate (10:1, 600 mL). The organic solution was washed with water (250 mL) and brine (250 mL), dried over Na2SO4, filtered and concentrated to dryness to give the title compound (11 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J=7.8, 1.5, 1H), 7.60 (dd, J=7.8, 1.5, 1H), 7.41 (m, 1H), 7.25 (m, 1H), 3.68 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:40][CH:39]2[CH2:41][C:42]([O:44]CC)=[O:43])=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>C1COCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:40][CH:39]3[CH2:41][C:42]([OH:44])=[O:43])=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCO)n1
Reactant: CCOC(=O)CC1CC1c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc(C3CC3CC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a solution of 2-[6-(methylamino)pyridin-2-yl]ethanol (1 g, 6.6 mmol) and PPh3 polymer bound (1.4 g, 9.9 mmole) in dry THF (50 mL) was added ethyl [(+)-2-(4-hydroxyphenyl)cyclopropyl]acetate (1.4 g, 6.6 mmol) from example 1 step 1, followed by diisopropyl azodicarboxylate (1.5 ml, 7.7 mmol). The reaction mixture was stirred at room temperature. After 18 hours, PPh3 polymer was filtered through celite and washed with excess THF. Filtrate was concentrated. The concentrated residue was dissolved in 1:1/acetonitrile:water (40 ml) and treated with LiOH (1 g). Reaction was heated two hours at 55° C. then cooled to room temperature. Reaction was acidified by adding TFA and purified on reverse phase HPLC twice to give 0.45 g (15%) of title compound. 1H NMR (400 MHz, CD3OD) δ 7.8 (m, 1 H), 7.0 (d, 2 H, J=8.6 Hz), 6.9-6.6 (m, 4 H), 4.26 (t, 2 H, J=6 Hz), 3.21 (t, 2 H, J=6 Hz), 3.0 (s, 3 H), 2.35-2.33 (m, 2 H), 1.71-1.67 (m, 1 H), 1.21-1.18 (m, 1 H), 0.89-0.76 (m, 2 H). HRMS calcd for C19H22N2O3 (M+H): 327.1703. found 327.1677.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[OH:38][C:34]1[CH:33]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (40 mg, 0.3665 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 70% yield (0.103 g, 0.2087 mmol).
Reaction SMILES: O[C:2]1[C:3](=[O:12])[N:4]([CH2:9][CH2:10][CH3:11])[C:5](=[O:8])[NH:6][CH:7]=1.BrN1C(=O)CCC1=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>C(O)C>[CH2:9]([N:4]1[C:3](=[O:12])[C:2]2[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28][C:7]=2[NH:6][C:5]1=[O:8])[CH2:10][CH3:11]
Reactant: Nc1ccccc1S
Reactant: CCCn1c(=O)[nH]cc(O)c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: CCCn1c(=O)[nH]c2c(c1=O)Nc1ccccc1S2
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of the 5-hydroxy-3-propylpyrimidine-2,4(1H,3H)-dione (0.85 g) in ethanol (40 ml), N-bromosuccinimide (0.98 g) was added in portions at room temperature. The mixture was stirred for 30 min. 2-Aminobenzenethiol (0.94 g) was added and the mixture was heated at reflux for one hour. After cooling, the precipitate was collected to give 1,5-dihydro-3-propyl-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (1.20 g, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH-:11].[Na+]>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(COCc2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Sordaricin benzyl ester (161.2 mg) was dissolved in 6 mL of N,N-dimethylformamide and p-methoxybenzyl chloride (1 mL) was added followed by excess sodium hydroxide (50 mg of a 60% dispersion in mineral oil). The mixture was stirred overnight. The mixture was diluted with ether and carefully washed with water. The ether layer was dried over anhydrous sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel chromatography to give 192.5 mg (93%) of the p-methoxybenzyl ether.
Reaction SMILES: Cl[CH:2]([CH3:21])[C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:2]([CH3:21])[C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25][CH2:24]1
Reactant: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reactant: CN1CCNCC1
Product: CC(C(=O)N1c2ccccc2C(=O)Nc2cccnc21)N1CCN(C)CC1
Yield: 49 %

Procedure:
Using the procedure of Example 5, the product of Step A was reacted with 1-methyl-piperazine to obtain a 49% yield of 5,11-dihydro-11-[2-(4-methyl-1-piperazinyl)-propionyl]-6-H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 223°-224° C. after crystallization from ethyl acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1>[CH2:24]([N:27]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2ccccc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 67 %

Procedure:
0.30 g (0.00091 mol) of 3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.5 ml (0.0183 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents and the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent. There was obtained 0.24 g (67%) of 3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a white solid. An analytical sample was recrystallized from diisopropyl ether and gave white crystals; m.p. 109°-110°.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[CH2:11]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([C:14]1[C:20]([OH:21])=[N:5][C:6]2[N:7]([N:8]=[CH:9][CH:10]=2)[C:15]=1[OH:16])[CH:12]=[CH2:13]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Product: C=CCc1c(O)nc2ccnn2c1O
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To an ethanolic solution (0.2 L) containing sodium ethoxide (7.8 g, 0.11 mol), 3-aminopyrazole (5.0 g, 0.6 mol) and diethyl allylmalonate (12 mL, 0.61 mol) were added at room temperature. The resultant mixture was heated under reflux for 24 hr. After the mixture was cooled down to room temperature, the solvent was distilled off. The residue was dissolved in water (150 mL) and the aqueous solution was washed with ethyl acetate. This aqueous layer was acidified by adding 6 mol/L hydrochloric acid, and the resultant precipitate was collected by filtration and dried under reduced pressure to obtain 6-allyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine (9.3 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:24][NH:25]C=O>>[CH2:19]([O:18][C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])[CH2:6]2)=[CH:11][C:10]=1[C:14]([NH:25][CH3:24])=[O:15])[CH3:20]
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)OC)cc2C1
Reactant: CNC=O
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NC)cc2C1

Procedure:
Using procedure 41, methyl 2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxylate (77, 0.32 g, 1 mmol) was treated with N-methylformamide (0.58 mL, 10 mmol). Chromatographic purification yielded pure product 83 as a oil which was converted into the HCl salt and crystallized from EtOAc/MeOH to give a white solid (m.p. 156-159° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:21](O)[C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 53.9 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2 -methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.11 g, 0.19 mmoles), CH2Cl2 (5 ml), triethyl silane (0.31 ml, 1.9 mmoles) and boron trifluoride etherate (0.12 ml, 0.97 mmoles). Flash chromatography (35% EtOAc/hexanes) provided 58 mg (53%) of the title compound as a tan solid.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][O:13][C@@:14]1([C:22]#[CH:23])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1.[CH:24]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([OH:32])[C:23]#[C:22][C@:14]2([O:13][CH3:12])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C#C[C@@]1(OC)CN2CCC1CC2
Reactant: O=C(c1ccccc1)C1CCCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCCC2)CN2CCC1CC2
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A 1.6 N solution of BuLi in hexane (41.7 ml, 66.7 mmol) was added dropwise to a solution of (3R)-3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl methyl ether 53 (11 g, 66.7 mmol) in THF (100 ml) cooled at −5° C. After stirring for 10 minutes, the medium was cooled at −15° C., and a solution of cycloheptyl(phenyl)methanone 44 (14.2 g, 70.2 mmol) in THF (50 ml) was slowly added. The cooling bath was removed and the reaction was allowed to gradually warm to room temperature during 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography over silica gel (CH2Cl2/EtOH/NH4OH 94/6/1). 1-cycloheptyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 116 was obtained as a white solid (20.35 g, 83%, mixture of diastereomers).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH:30]=O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH2:30][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: O=CCc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: O=C1CN(CCc2ccc([N+](=O)[O-])c(F)c2)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (3-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 417 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7](C)[C:4]=1[CH:5]=O.[C:18](O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:8]1([CH:7]=[C:4]([CH3:5])[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]1[O:13][CH3:14])[CH:18]=[CH:19][C:20]([OH:22])=[O:21]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC1=C(OC)C(OC)C(C=CC(=O)O)(OC)C=C1C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
2,3,4,5-Tetramethoxy-6-methylbenzaldehyde (17.3 g, 72.1 mmol), malonic acid (22.5 g, 216 mmol) and piperidine (1.7 ml) were dissolved in pyridine (50 ml). The reaction was conducted for 5 hours, while the temperature was gradually raised from 50° C. to 100° C. The solvent was removed under reduced pressure. The residue was acidified with 2N hydrochloric acid, extracted and concentrated. Recrystallization of the product from ethyl acetateisopropyl ether gave 1,2,3,4-tetramethoxy-5-methylcinnamic acid (Compound 20, 14.3 g, 70%). m.p. 117°-118° C. δ 2.31 (3H), 3.78 (3H), 3.83 (3H), 3.90 (3H), 3.96 (3H), 6.59 (1H), 7.94 (1H), 11.2 (1H).
Reaction SMILES: CN(C)[C:3]([S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:9]2)=O.[OH-].[K+].COS(OC)(=O)=O>CO>[CH3:3][S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2cc(SC(=O)N(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: CSc1ccc2cc(C(=O)O)ccc2c1
Temperature: 5 °C
Yield: 91.4 %

Procedure:
A suspension of 158 (6.36 g, 22-mmol) in a mixture of aqueous KOH (5N, 340 mL, 1.7 mol) and MeOH (205 mL) was stirred at reflux for 3 h, then cooled to 5° C. and treated dropwise with Me2SO4 (26 mL. 275 mmol). After stirring at room temperature for a further 4 h the mixture was concentrated to half volume, acidified with dilute aqueous HCl, and the precipitated product was crystallised from EtOAc/hexane to give 6-(methylsulfanyl)-2-naphthoic acid (159) (4.39 g, 91%) as a white solid: mp (MeOH) 231-233° C.; 1H NMR [(CD3)2SO] δ (CO2H not observed) 8.53 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.96 (dd, J=8.6, 1.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 7.47 (dd, J=+8.7, 1.9 Hz, 1H), 2.61 (s, 3H). Anal. (C12H10O2S) C, H.