Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]=O>C(O)=O>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]2[CH2:13][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Reactant: C=O
Solvent: O=CO
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C)CC3)C2)cn1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (50 mg, 0.162 mmol) in formic acid (0.25 mL) was added formaldehyde (37% aq. sol., 0.097 mL, 1.296 mmol) and the reaction mixture was heated at 100° C. for 5 hours. Volatiles were then removed at reduced pressure to give the title compound (38 mg, 75%) after purification by silica FCC (eluting with 95:4.5:0.5 to 92.5:7.25:0.75 gradient of DCM/MeOH/NH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 1.55 g of 4(S)-(3-hydroxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester [177198-40-2] in 22 ml of methylene chloride at room temperature under argon is added 3.49 ml of triethylamine and 0.855 ml of methanesulfonyl chloride. The mixture is stirred at room temperature for 13 hours. The reaction is quenched by addition of 35 ml of 0.5M HCl. The mixture is extracted with methylene chloride. The organic layer is concentrated, dried over sodium sulphate and concentrated. The crude title compound is obtained as an orange oil. Rf=0.52 (1:1 EtOAc-heptane); Rt=3.64 (gradient I).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)O)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].N1C=CC=CC=1.[F:40][C:41]([F:52])([F:51])[C:42]([O:44]C(=O)C(F)(F)F)=[O:43].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH2:17][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]([O:44][C:42](=[O:43])[C:41]([F:52])([F:51])[F:40])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCC(Oc1ccccc1)(C(=O)OCC)C(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(OC(=O)C(F)(F)F)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-hexanoic acid ethyl ester (13.4 mmol) in anhydrous CH2Cl2 (100 mL) and pyridine (134 mmol) was cooled to 0° C. and treated with trifluoroacetic anhydride (26.9 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. An aqueous solution of 1N HCl (150 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 2-(4-benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acid ethyl ester as an oil.
Reaction SMILES: C([OH:3])C.[OH-].[Na+:5].[OH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:23])=[C:18]([O:30][CH3:31])[CH:17]=3)=[C:11]2[N:10]=[CH:9][N:8]=1>O>[OH2:3].[OH2:6].[CH3:31][O:30][C:18]1[CH:17]=[C:16]([C:15]2[CH:14]=[N:13][N:12]3[C:7]([O-:6])=[N:8][CH:9]=[N:10][C:11]=23)[CH:21]=[CH:20][C:19]=1[S:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[Na+:5]
Reactant: COc1cc(-c2cnn3c(O)ncnc23)ccc1S(=O)c1ccccc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(-c2cnn3c([O-])ncnc23)ccc1S(=O)c1ccccc1

Procedure:
In a mixed solution prepared from 50 ml of ethanol, 10 ml of water and 145 mg of sodium hydroxide were dissolved 1.3 g of (-)-4-hydroxy-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine with stirring and the solvent was then distilled off under reduced pressure. After addition of 100 ml of ethyl acetate, the mixture was refluxed for 30 minutes. After cooling, the crystals were recovered by filtration and dried to give sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine-4-olate dihydrate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[CH:52]=[CH:51][C:35]5[NH:36][C:37]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)=[N:38][C:34]=5[CH:33]=3)[CH:26]=[CH:25]4)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:28]1[C:29]2[C:24](=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][C:16]=4[CH:18]=3)=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[C:32]1[CH:52]=[CH:51][C:35]2[NH:36][C:37]([CH:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[N:38][C:34]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2cc(-c3ccc4cc(-c5ccc6nc(C7CCCN7C(=O)OC(C)(C)C)[nH]c6c5)ccc4c3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3ccc4[nH]c(C5CCCN5)nc4c3)ccc2cc1-c1ccc2[nH]c(C3CCCN3)nc2c1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl 2-(5-(6-(2-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate (591 mg. 0.844 mmol) and TFA (2 mL) in CH2Cl2 (10 mL) was stirred at ambient conditions for 2 hours. The volatile component was removed in vacuo and the resulting material was loaded onto a MCX column, flushed with methanol, released with 2.0 M NH3/methanol elution) and concentrated to provide 5,5′-(2,6-naphthalenediyl)bis(2-(2-pyrrolidinyl)-1H-benzimidazole) (419 mg) as tan solid. LC-MS retention time 1.02 min; Calcd. for C33H31N5: 498.25 Found m/z 499.25 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.84-7.92 (m, 1H), 7.73-7.81 (m, 2H), 5.08 (t, J=7.6 Hz, 1H), 3.56-3.66 (m, 1H), 3.48-3.56 (m, 1H), 2.62-2.71 (m, 1H), 2.36-2.47 (m, 1H), 2.19-2.36 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24](=O)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1ccccc1Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(2-chloro-phenyl)-butan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][N:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:31][N:30]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1ccc(CCl)cn1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (obtained in Example 93, step 6) by alkylation with ethyl-5-(chloromethyl)-pyridine-2-carboxylate [CAS Reg. No. 39977-48-5]. MS (m/e)=509.1 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg, 1.4 mmol) and 5-bromo-pyridin-3-ol (248 mg, 1.4 mmol) are added to a solution of PPh3 (606 mg, 2.3 mmol) in THF (30 mL). Then diisopropyl azodicarboxylate (462 mg, 2.3 mmol) is added and the mixture is stirred at room temperature for 16 hrs. The mixture is then diluted with DCM, washed with water, dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography to give 250 mg of 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH2:20]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:7]([CH:3]1[C:4]([CH3:5])([CH3:6])[C:2]1([CH3:1])[CH3:10])=[O:9]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2ccccc2s1
Product: CC1(C)C(C(=O)Nc2nc3ccccc3s2)C1(C)C
Yield: 27.1 %

Procedure:
A mixture of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5 mmol) and benzothiazol-2-ylamine (0.58 g, 3.9 mmol) were processed as in Example 9A. Purification by column chromatography (SiO2, 20-40% ethyl acetate/hexanes gradient) afforded 0.26 g (27%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.22-1.27 (m, 6H), 1.36 (s, 6H), 1.67 (s, 1H), 2.07-2.18 (m, 2H), 3.34 (s, 3H), 3.41 (t, J=5.8 Hz, 2H), 4.39-4.53 (m, 2H), 7.20-7.26 (m, 1H), 7.37-7.42 (m, 2H), 7.60 (d, J=7.5 Hz, 1H); MS (DCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c2) the title compound is obtained as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=NN(C)C)[CH:6]([CH3:15])[CH2:5]2.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:17])[CH:6]([CH3:15])[CH2:5]2
Reactant: O=S(=O)(O)O
Reactant: CC1Cc2cc(Cl)ccc2C1=NN(C)C
Product: CC1Cc2cc(Cl)ccc2C1=O

Procedure:
5.5 g of N′-(5-chloro-2-methylindan-1-ylidene)-N,N-dimethylhydrazine are emulsified in 100 ml of 2N sulfuric acid and boiled under reflux for 4 h. The cooled reaction mixture is cautiously extracted with ethyl acetate; the organic extract is extracted several times with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, dried in vacuo and chromatographed on silica gel with ethyl acetate/hetpane ⅕. 5-Chloro-2-methylindan-1-one is obtained as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3]([C:20]([OH:22])=[O:21])=[C:4]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Product: Cn1c(C(=O)O)c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
The title compound was prepared from ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 3.94 (s, 3H, 7.00-7.10 (m, 1H, 7.10-7.27 (m, 3H, 7.27-7.45 (m, 3H, 7.45-7.62 (m, 5H, 9.86 (s, 1H), 12.97 (br s, 1H; MS (ESI) m/z 461 [M-H]−; HRMS calcd for C26H27N2O4S: 463.1689; found (ESI+): 463.1681; Anal. calcd for C26H26N2O4S.0.15H2O: C, 67.12; H, 5.70; N, 6.02. Found: C, 67.05; H, 5.42; N, 5.88.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[CH3:25][C:24]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: c1ccc(OCC2CO2)c(CCCc2cccc3[nH]ccc23)c1
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccccc1CCCc1cccc2[nH]ccc12
Temperature: 80 °C

Procedure:
A mixture of 2.2 g of the product of Step B and 7.6 ml of tert.-butylamine and 20 ml of methanol was heated at 80° C. for 2 hours and was evaporated to dryness. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 2.7 g of 1-(1,1-dimethylethylamino)-3-[2-[3-[1H-indol-4-yl]-propyl]-phenoxy]-2-propanol melting at 96° C.
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14]C)=O)=O.O.[NH2:17][NH2:18]>>[C:12]1(=[O:14])[C:4]2[CH:5]=[C:6]3[N:11]([C:3]=2[CH:1]=[N:18][NH:17]1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Reactant: NN
Solvent: O
Product: O=c1[nH]ncc2c1cc1n2CCCC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 193d (600 mg, 2.9 mmol) and hydrazine hydrate (20 mL). The reaction mixture was heated at 100° C. for 4 hours. After this time the reaction was cooled to room temperature and filtered to afford 193e as a yellow solid (413 mg, 75%). MS-ESI: (M+H)+ 190.1. 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.24 (s, 1H), 6.33 (s, 1H), 4.16 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.84-1.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([CH3:21])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[C:20]([CH3:21])[C:13]=12
Reactant: [H][H]
Reactant: Cc1c[nH]c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12

Procedure:
23 mg (80 μmol) of N-(2-fluoro-4-nitrophenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 12 ml of ethanol. 19 mg (19 μmol) of 10% palladium-on-carbon are added and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure overnight. The mixture is filtered through Celite and the solvent is removed under reduced pressure.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([CH:15]([SH:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:16][CH:15]([S:17][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(S)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(SN1C(=O)CCC1=O)c1ccccc1
Yield: 36.8 %

Procedure:
To a suitable reactor equipped with temperature controlling means and stirring means, there are charged, while maintaining the temperature at about room temperature, N-chlorosuccinimide (about 0.30 mole) in 400 ml of benzene and 1-phenylethanethiol (about 0.30 mole) in 50 ml of benzene. After stirring the reaction mixture 10 minutes, triethylamine (0.32 mole) in 50 ml of benzene is added dropwise. The benzene mixture is stirred one hour and then filtered. The filtrate is washed three times with 250 ml portions of water and then subjected to vacuum with heating to strip off volatile components. A crystalline residue is recrystallized from ethanol to give 26 grams of N-(α-methylbenzylthio)succinimide, m.p. 121°-125° C.
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 45 %

Procedure:
The O-alkylation procedure described for 190 was used. To a suspension of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (0.510 g, 1.74 mmol), K2CO3 (0.300 g, 2.17 mmol), and acetone (75 mL) was added ethyl 2-bromo-2-methylpropanoate (0.0.382 mL, 2.6 mmol) at RT. The reaction mixture was refluxed for 48 h and filtered. The filtrate was concentrated and purified to afford 0.320 g (45%) of the title compound 225 as a white foam. In addition, 0.210 g of unreacted starting material was recovered. 1H NMR (300 MHz, CD3OD): δ 7.02 (d, J=1.8 Hz, 2H), 6.99 (d, J=2.1 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.73 (d, J=1.5 Hz, 2H), 4.71 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.30 (br d, J=3.3 Hz, 4H), 1.59 (s, 6H), 1.58 (br s, 8H), 1.24 (t, J=6.9 Hz, 3H). LCMS (ESI): m/z 407 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9](=[O:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)c1ccccc1)C(O)CF
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(NC(=O)c1ccccc1)C(=O)CF
Yield: 95 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one (273 mg, 0.64 mmol) was added in one portion to a stirred solution of 3-benzoylamino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (100 mg, 0.32 mmol) (prepared from benzoic acid and 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester using standard coupling procedures eg. HOBT, DMAP, and EDC) in dry dichloromethane (DCM) (2 ml) at 0° C. The mixture was brought to room temperature (r.t.) during 16 h, diluted with EtOAc, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulphate. The organic layer was removed and the aqueous layer re-extracted with EtOAc. The combined organic organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (30% EtOAc in hexane) to afford the title compound as a colourless gum (94 mg, 95%): 1H NMR (CDCl3) δ 7.80 (2H, m), 7.50 (4H, m), 5.2 (3H, m), 2.95 (2H, m), 1.45 (9H, s); 13C NMR (CDCl3) δ 203.19, 203.02, 171.02, 167.57, 133.54, 133.04, 132.60, 129.16, 127.97, 127.53, 85.52, 83.70, 82.80, 53.13, 53.03, 36.63, 36.61, 28.44, 28.37; 19F NMR (CDCl3) δ −232.09(t, J 49 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Br:16]Br>CC(O)=O>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:3]([CH3:15])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Cc1c(Cl)cccc1NC(=O)C(C)(C)C
Solvent: CC(=O)O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Br)c1Cl

Procedure:
N-(3-Chloro-2-methylphenyl)-2,2-dimethylpropanamide (0.5 g, 2.2 mmol) and bromine (1.4 g, 8.8 mmol) were combined in AcOH (25 mL) at rt for 2 h. The residue resulting from concentration was purified by flash chromatography (20-60% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 305 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:22]2[CH2:26][C:25]([F:28])([F:27])[CH2:24][N:23]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[N:8]([CH3:21])[C:9](=[O:20])[C:10]=1[O:11]C(=O)C1C=CC=CC=1)=O.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>CO>[CH2:32]([O:31][C:29]([N:23]1[CH2:24][C:25]([F:28])([F:27])[CH2:26][C@H:22]1[C:7]1[N:8]([CH3:21])[C:9](=[O:20])[C:10]([OH:11])=[C:5]([C:3]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:2])[N:6]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)c1nc([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: Cn1c([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]4,4-difluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate in dry MeOH was treated with 4-fluorobenzyl amine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and the residue was taken up in ethyl acetate, washed with HCl 1N, brine, dried over Na2SO4. The filtrate was concentrated in vacuo and triturated with ethyl ether to obtain the title compound as a 1.5:1 mixture of two rotamers by NMR.