Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([O:3]CC)=[O:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1nnc(S)o1

Procedure:
A solution of 3.15 g (0.017 mol) of 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol in 25 ml of water and 25 ml of ethanol was stirred for 5 hours while maintaining the pH at 10-11 by addition of 10% aqueous sodium hydroxide solution. The mixture was neutralized to pH 7.0 then evaporated to dryness. The residue was dissolved in 15 ml of water, 50 ml of ethyl acetate was added and the solution was acidified to pH 1.5 with 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated to give a residue which was recrystallized from ether-cyclohexane to give 2-carboxymethyl-1,3,4-oxadiazole-5-thiol, m.p. 167° -169° (dec.)
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][NH:11]3)=[N:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([CH2:30][OH:31])=[N:27][C:26]=2[C:32](O)=[O:33])=[CH:21][CH:20]=1>>[F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:32]([C:26]3[N:27]=[C:28]([CH2:30][OH:31])[S:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:33])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Reactant: Fc1cc2nc(C[C@@H]3CCCN3)[nH]c2cc1F
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCC[C@H]1Cc1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound (65 mg) was prepared from 5,6-difluoro-2-(S)-1-pyrrolidin-2-ylmethyl-1H-benzoimidazole, D27 (153 mg) and 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (205 mg) according to a procedure similar to that for Example 4.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-:33].[Na+].[Na+].OO>C(O)C>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([NH2:24])=[O:33])[CH:8]=2)[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ccccn1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a suspension of 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile (0.24 g, 0.57 mmol) in ethanol (20 mL) was added 3 M aqueous sodium carbonate (2 mL) and 30% w/w aqueous hydrogen peroxide (2 mL). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was triturated in water to afford 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide (0.23 g, 93%) as a colorless solid: mp 220-222° C. (water); 1H NMR (300 MHz, CDCl3) δ 8.46-8.42 (m, 1H), 7.82 (s, 1H), 7.81-7.74 (m, 2H), 7.65 (d, J=1.5 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.0, 5.0 Hz, 1H), 7.19 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H), 5.14-4.97 (ABq, 2H), 4.81-4.68 (ABq, 2H), 4.19-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 167.6, 155.4, 155.1, 149.7, 145.7, 144.7, 138.3, 137.6, 132.4, 129.4, 129.2, 123.3, 123.3, 122.3, 121.6, 112.1, 109.3, 99.2, 79.8, 64.7, 64.1, 57.7, 45.3; MS (ES+) m/z 429.9 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: N#Cc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: N#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile (300 mg, 0.88 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (206 mg, 0.97 mmol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
The bis(4-acetyloxyphenylsulfonyl)methane in Synthesis Example 3, 4.5 g (0.011 mol), was dispersed in 49 g of dichloromethane. To the dispersion was added 2.5 g (0.016 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring at room temperature, 3.0 g (0.015 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to the dispersion, and after 5 minutes, 50 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 50 g of water. The organic layer was concentrated and 8 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 10 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 1.5 g (yield 31%) of fine yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]2[C:5]([C:6]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1.N>O.C(O)C>[Br:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:5]([C:6]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Br)ccc12
Agent: N
Solvent: O
Solvent: CCO
Product: CCCC(=O)Nc1n[nH]c2c(N)c(Br)ccc12
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4.25 g of ferrous sulphate heptahydrate dissolved in 25 cm3 of water are added dropwise to 510 mg of N-[6-bromo-7-nitro-1H-indazol-3-yl]butanamide, described in Example 29, in 20 cm3 of ethanol cooled to about 5° C. The temperature rises to about 28° C., the mixture is left stirring for 30 minutes, 5.2 cm3 of 28% aqueous ammonia are then added, the mixture is refluxed for 2 hours, a further 2×1.5 cm3 of 28% aqueous ammonia are then added and the mixture is left stirring for a further 10 minutes and filtered while hot through a sinter funnel packed with Celite. The precipitate is rinsed with 20 cm3 of methanol and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 50 cm3 of ethyl acetate and washed with 25 cm3 of saturated sodium hydrogen carbonate solution and then with 25 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate and concentrated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 50° C.), 55 mg of N-[6-bromo-7-amino-1H-indazol-3-yl]butanamide are thus obtained in the form of a mauve-coloured solid.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:29])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:32].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:29][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:32])[CH3:5]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)=NN(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The above hexanone hydrazone (1 mmol) is dissolved in 10 ml of methanol with 2 ml of 2M pH 7 phosphate buffer, and a solution of sodium periodate (2.2 mmol) in 2 ml of water is added, with stirring. The mixture is stirred for 3 hours, after which the solvent is removed and the residue is extracted with chloroform. The extract is washed with water and dried and the solvent is removed to give 4-hydroxy-5-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-hexanone (C'; Q1 is N, Y is chloro, Z is trifluoromethyl, R1 is methyl and R2 is methyl).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][C:14]([NH:16][C@@H:17]2[C:44](=[O:45])[N:19]3[C:20]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)=[O:33])=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:22][S:23][C@H:18]23)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]=1>ClCCl>[O:45]=[C:44]1[N:19]2[C@H:18]([S:23][C@@H:22]3[C:21](=[C:20]2[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[O:33])[C@@H:51]2[C@H:46]3[CH2:47][CH2:48][CH2:49][CH2:50]2)[C@@H:17]1[NH:16][C:14](=[O:15])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: C1=CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3[C@H]4CCCC[C@H]4[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 16 h
Yield: 44.2 %

Procedure:
Potassium carbonate (9.5 mg, 0.068 mmol) was added to a solution of p-methoxy-benzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (20 mg, 0.034 mmol) and cyclohexene (17.3 μl 0.17 mmol) in dichloro-methane (1.5 ml). The mixture was stirred for 16 h, then chromatographed to give the title compound (7.8 mg, 44%) as a cream solid, mp. 234°-236° C. (EtOAc) (Found: M+, 518.1882. C29H30N2O5S requires M, 518.1875); νmax (CH2Cl2) 1784, 1718, 1685 cm-1 ; δH (CDCl3) 1.00-1.99 (8H, m), 2.39 (1H, br q, J 8.2), 3.47 (1H, taut, J 9.3, 8.4, 2.6), 3.63 (2H, ABq, J 16.3), 3.80 (3H, s), 4.26 (1H, dd, J 8.7, 2.6), 4.90 (1H, d, J 4.9), 5.17 (2H, ABq, J 11.9), 5.75 (1H, dd, J 8.9, 4.9), 5.98 (1H, d, J 8.8), 6.86 (2H, d, J 8.7), 7.25-7.37 (7H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1[CH:5]=O.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1/[CH:5]=[CH:17]/[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:18]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2cccs2)cc1C=O
Product: COc1ccc(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2-methoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-45A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 195–196° C. 1H-NMR (DMSO-d6) δ 8.23–8.20 (m, 3H), 8.08–7.96 (m, 4H), 7.67 (dd, J=2.1, 6.8 Hz, 1H), 7.55 (d, J=3.8 Hz, 1H), 7.49 (d, J=5.1 Hz, 1H), 7.16–7.11 (m, 2H), 3.90 (s, 3H). MS m/z=364 (M+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([N:28]1[CH:33]=[C:32]([C:34](O)=[O:35])[C:31](=[O:37])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:29]1=[O:45])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:34]([C:32]2[C:31](=[O:37])[N:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:29](=[O:45])[N:28]([CH2:26][CH3:27])[CH:33]=2)=[O:35])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(C)C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=173-175° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.80 (s, 1H), 8.45 (d, 1H, J=6 Hz), 7.76 (dd, 1H, J=2, 8 Hz), 7.68 (d, 1H, J=2 Hz), 7.55 (s, 1H), 7.46-7.33 (m, 5H), 7.16 (d, 1H, J=8 Hz), 6.36 (d, 1H, J=5 Hz), 4.01 (q, 2H, J=8 Hz), 3.94 (d, 6H), 2.99 (m, 1H), 1.3 (t, 3H, J=7 Hz), 1.14 (d, 6H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc5ccccc5c4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc5ccccc5c4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.95-7.34,(14H, m), 4.87-4.71,(2H, m), 2.99-2.94,(3H, m), 2.55,(3H, s), 2.33-2.28,(3H, m). LCMS; retention time 3.66 min, MH+ 448.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.45 (m, 2H), 7.3 (m, 3H), 7.2 (s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3433, 3202 (br), 1630, 1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e 349, 351, 353.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:43]1[NH:44][CH:45]=[C:46]([C:48](O)=[O:49])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:38][C:36]([O:39][C:40]([N:42]([C:43]1[NH:44][CH:45]=[C:46]([C:48]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:49])[N:47]=1)[C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[O:41])([CH3:35])[CH3:37]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)O)c[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (0.035 g, 0.183 mmol) and HOBT (0.025 g, 0.183 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.048 g, 0.153 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-4-carboxylic acid (0.050 g, 0.153 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated aqueous sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate as an oil. Trifluoroacetic acid (0.3 mL, 3.89 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.066 g, 0.106 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight, concentrated and purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.017 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.18 (m, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 7.44-7.50 (m, 2H), 7.30 (t, 1H), 7.10 (s, 1H), 5.45 (br. s., 2H), 4.44 (d, 2H). MS m/z 420 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]12[CH2:18][CH:17]1[C:16](=[O:19])[NH:15][C:14]2=[O:20].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:15]1[C:16](=[O:19])[CH:17]2[CH:13]([CH2:18]2)[C:14]1=[O:20]
Reactant: O=C1NC(=O)C2CC12
Reactant: OCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C2CC2C(=O)N1CCCCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Diethyl azodicarboxylate (0.94 g) was added to a mixture of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.5 g), 1,7-heptanediol (2.46 g), triphenylphosphine (1.42 g) and 4 angstrom sieves (1.5 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days and was then filtered. The solids were washed with ethyl acetate (2×50 ml) and the combined filtrates were evaporated in vacuo. The residue was purified by chromatography on silica using 60-70% ethyl acetate/hexane as eluant, followed by kugelrohr distillation (b.p. 200-220° C. @ 1 mmHg) to give the subtitle compound as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]#[C:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>CCOC(C)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#Cc2cccc(CO)c2)c1
Agent: O=[Pt]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 6.25 h

Procedure:
In a 50 mL round-bottom flask, a solution of 3-[[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]ethynyl]phenylmethanol in EtOAc was hydrogenated over PtO2 with stirring at room temperature for 6.25 h. TLC (silica gel, EtOAc/hexane 3:1) showed a new spot (Rf 0.15) in place of the starting material (Rf 0.3), which was accompanied by a nonpolar impurity. The solution was concentrated and filtered over silica gel (11×1.3 cm, EtOAc). Evaporation of the product-containing fractions gave a quantitative yield of crude product, which by 1H NMR was shown to be a mixture of two major components in a molar ratio of approx. 4.5-5:1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17](=[O:25])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:26]>CC(O)C>[NH2:26][C:20]1[C:19]2[N:18]([C:17](=[O:25])[NH:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: N
Reactant: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Solvent: CC(C)O
Product: Nc1nccn2c(=O)[nH]c(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 110 °C

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-2H-imidazo[1,5-a]pyrazin-3-one (100 mg, 0.28 mmol) in i-PrOH (4 mL) was saturated with NH3 at −20° C. and heated 110° C. in a sealed tube for 48 hours. The light brown reaction mixture was partitioned in water and DCM and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 8% MeOH in DCM], resulting in the title compound as a pale brown solid; 1H NMR (DMSO-d6, 400 MHz) δ=5.16 (s, 2H), 5.86 (brs, 2H), 6.70 (d, J=5.2 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 7.07-7.14 (m, 2H), 7.24 (brt, J=2 Hz, 1H), 7.32-7.49 (m, 7H); MS (ES+): m/z=333.21 (100) [MH+], HPLC: tR=2.05 min (MicromassZQ, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=O>C1COCC1.N1C=CC=CC=1>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A solution of 1 g (3.86 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 2 ml of THF and 5 mL of pyridine was treated with 0.44 mL (4.63 mmol) of Ac2O and stirred for 2 hrs at 60° C. The solvent was evaporated and the crude distributed between a diluted aqueous solution of HCl and Et2O. the combined organic phases were dried over Na2SO4 and the solvent evaporated. The residue was dissolved in 5 mL of THF, treated with 7.7 mL of a 1M BH3*THF-solution in THF and refluxed for 2 hrs. The solvent was evaporated and the residue distributed between a diluted aqueous solution of NaOH and Et2O. The aqueous phase was then acidified by addition of an aqueous solution of HCl to a pH of ca. 7 and extracted with Et2O. The combined organic phases were dried over Na2SO4 and the solvent evaporated to give 1.07 g (96%) of crude 2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow solid, MS: 288 (MH+).