Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].ClCCl>O1CCCC1.CO.ClCCl>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O
Yield: 88.9 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) was dissolved in tetrahydrofurane (5 ml). Sodium hydrogencarbonate (0.053 g; 0.631 mmole) was added and the mixture was stirred for a little while. 4-tert-Butylbenzoyl chloride (0.118 g; 0.6 mmole) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel(Isolute, SI) using dichloromethane:heptane (1:1), then dichloromethane and finally methanol: dichloromethane (1:99) as eluants gave 0.238 g (89% yield) of 3-{4-[2-{4-(4-[tert-butyl]benzoyl)aminophenyl}ethoxy]phenyl}-2-(S)-ethoxypropanoic acid.
Reaction SMILES: [BH4-].[Na+].CC([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:13]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([CH:28]([OH:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (20.52 mg, 0.543 mmol) was added to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 75) (260 mg, 0.452 mmol) in MeOH (5 mL) at 25° C. under N2. The reaction mixture was stirred at room temp for 2 h. About ˜⅔ of the methanol was evaporated in vacuo and the residue was treated slowly with 1M HCl (5 mL). The product was extracted with EtOAc (2×40 mL) and the combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford a yellow oil. 4N HCl in Dioxane (2 mL, 8.00 mmol) was added to the residue at 25° C. and the reaction mixture was stirred for 30 min. The crude sample was loaded straight on to a pre-washed (MeOH)SPE sulphonic acid (SCX-2) cartridge (20 g). The SCX cartridge was washed with 2 column volumes of MeOH and the product was collected by washing with 3 column volumes of 2N Ammonia in MeOH. The appropriate fractions were combined and evaporated in vacuo to give the title compound (235 mg, 91) %. LCMS (System A) RT=0.77 min, ES+ve m/z 477/479 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[CH:13]=[CH:12][S:11][C:7]=2[N:8]=[CH:9][N:10]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH:1]([NH:4][C:5]1[C:6]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[S:11][C:7]=2[N:8]=[CH:9][N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ncnc2sccc12
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)Nc1ncnc2sc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-isopropylaminothieno[2,3-d]pyrimidine (4.0 g, prepared as described in Example 5) and concentrated sulphuric acid (20 ml) was cooled to 0° and treated dropwise with a mixture of concentrated nitric acid (2.2 ml) and concentrated sulphuric acid (2.0 ml) whilst maintaining the temperature below 12° C. The mixture was allowed to stir at room temperature for a further one hour, poured into ice-water and neutralised with sodium carbonate. The precipitate was filtered off, washed with water and dried to give 4-isopropylamino-6-nitrothieno[2,3-d]pyrimidine (4.58 g, m.p. 200°) (Compound No. 134).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:20](O)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](O)=[O:18])=[CH:9][CH:8]=1>C1COCC1>[C:10]1([CH2:17][OH:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:20][OH:21])=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(CO)c2ccccc12
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A dry 3-neck, 1 L flask equipped with a N2 inlet and dropping funnel is charged with dry THF (200 mL) and LiAlH4 (1.90 g, 0.050 mole). To the stirred mixture is added via the dropping funnel a hot solution of naphthalene-1,4-dicarboxylic acid (4.32 g, 0.020 mole) in THF (200 mL) over a period of about 1 hour. The resulting mixture is stirred without heating for 90 minutes and then is heated to reflux temperature. After 2 hours, additional LiAlH4 (40 mL of a 1.15M solution in THF) is added and refluxing continued for 90 minutes. The reaction is stirred at room temperature overnight, then is quenched carefully with THF-water (3:1), acidified to pH <4 with 2N hydrogen chloride, transferred to a separatory funnel and extracted (3 times) with ether. The combined ether extracts are washed with water (2 times), dried (sodium sulfate), filtered, and concentrated to give a white solid (3.68 g). The solid is crystallized from ethyl acetate-hexane, giving (2.68 g) as white crystals, mp 124°-126° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([N:6]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:7][C:8](=[O:33])[C@@H:9]([CH:14]([C:23](=[O:32])[NH:24][O:25]C1CCCCO1)[CH2:15]/[CH:16]=[CH:17]/[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C@@H:2]([C:4]([N:6]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:7][C:8](=[O:33])[C@@H:9]([CH:14]([C:23](=[O:32])[NH:24][OH:25])[CH2:15]/[CH:16]=[CH:17]/[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(C/C=C/c1cccs1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(C/C=C/c1cccs1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A solution of 0.180 g of (E)-2′-(D-alanyl)-2(R)-[1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.077 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by column chromatography on silica gel, using dichloromethane/methanol (95:5) for the elution, to give 0.056 g of (E)-2′-(D-alanyl)-2(R)-[1(RS)-(hydroxycarbamoyl)-4-(2-thienyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:15])[CH:4]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(-c2ccccc2)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1
Yield: 93 %

Procedure:
A magnetically stirred solution of 4-methoxybiphenyl-2-ylamine (25.27 g, 127 mmol) in CH2Cl2 (300 mL)/pyridine (300 mL) at 0° C. under nitrogen was treated with pivaloyl chloride via syringe (16.8 g, 17.2 mL, 139 mmol). The resultant suspension was stirred for 12 h at room temperature and concentrated in vacuo. The residue was digested with CH2Cl2 (300 mL), washed with 1 N HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL), brine (300 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 33.6 g (93%) of a white solid: 1H NMR (300 MHz, CDCl3) δ 1.07 (s, 9H), 3.83 (s, 3H), 6.69 (dd, J=8.5, 2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.29-7.47 (m, 5H), 7.53 (br s, 1H), 8.13 (d, J=2 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:23][C:24]3[CH:32]=[CH:31][C:27]4=[N:28][S:29][N:30]=[C:26]4[CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:9]([F:33])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[N:28]1[S:29][N:30]=[C:26]2[CH:25]=[C:24]([O:23][C:18]3[C:17]([C:15]([NH:14][CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:8][C:9]=4[F:33])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:32]=[CH:31][C:27]=12
Reactant: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.13) was prepared in a manner analogous to that described in Example 1, substituting (R)-2-[4-({[2-(benzo[2,1,3]thiadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([F:23])[CH2:22][O:21][CH2:20]4)=[CH:15][C:14]=3[O:24][CH3:25])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:77]([SH:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:77]([S:84][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([F:23])[CH2:22][O:21][CH2:20]4)=[CH:15][C:14]=3[O:24][CH3:25])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C2(F)COC2)ccc1-c1nc(C)nc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2(F)COC2)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
The reaction mixture from step 4 was treated with Pd2(dba)3 (0.023 g, 0.025 mmol), Xantphos (0.029 g, 0.051 mmol), and n,n-diisopropylethylamine (0.530 ml, 3.04 mmol), and was heated to 60° C. Benzyl mercaptan (0.120 ml, 1.012 mmol) was added, and the reaction mixture was allowed to stir for one hour at 60° C. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by silica gel column chromatography (0-75% EtOAc/heptane) gave 7-(benzylthio)-4-(4-(3-fluorooxetan-3-yl)-2-methoxyphenyl)-2-methylquinazoline (0.189 g, 0.423 mmol, 41.8% yield) with minor impurities. (M+H)+=447.0.
Reaction SMILES: [S:1]1[CH:5]=C[C:3]([CH2:6][CH2:7][P:8]([OH:21])([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])=[O:9])=[CH:2]1.S1C=CC(CCCP(O)(CC(C2C=CC=CC=2)C(O)=O)=O)=C1.C(P(O)(CC(CC1C=CC=CN=1)C(O)=O)=O)C1C=CC=CC=1>>[S:1]1[CH:5]=[C:6]([CH2:7][P:8]([OH:21])([CH2:10][CH:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([OH:14])=[O:13])=[O:9])[CH:3]=[CH:2]1
Reactant: O=C(O)C(CP(=O)(O)CCc1ccsc1)c1ccccc1
Agent: O=C(O)C(CP(=O)(O)CCCc1ccsc1)c1ccccc1
Agent: O=C(O)C(Cc1ccccn1)CP(=O)(O)Cc1ccccc1
Product: O=C(O)C(CP(=O)(O)Cc1ccsc1)c1ccccc1

Procedure:
3-[(3-thienyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid; 3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)methylpropanoic acid;
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[N:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1([CH3:30])[C:25]2[C:20]([O:19][C:16]3[N:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:14][N:15]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC1(C)COc2cccc(Oc3ncc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl[2-({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 142, 30 mg, 0.068 mmol) in dry Dichloromethane (DCM) (1.6 mL) at 0° C. TFA (0.4 ml, 5.19 mmol) was slowly added and the reaction mixture was stirred for 1 h at the same temperature. The solvent and the excess of TFA were evaporated end the residue was dissolved in DCM (5 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8-9. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (20 mg) as a white solid.
Reaction SMILES: Cl[CH:2]([C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH3:16])=[C:11]([Cl:17])[CH:10]=1)=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-:19].[Na+].[Na+]>Cl>[Cl:17][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[CH:2]([OH:19])[CH2:3][C:4]([OH:6])=[O:5])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)cc(C(=O)C(Cl)CC(=O)O)cc1Cl
Agent: Cl
Agent: [Na+]
Product: Cc1c(Cl)cc(C(=O)C(O)CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
2.96 g of 3-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid were added to 300 ml of a 10% w/v aqueous solution of sodium carbonate, and then the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was periodically checked by thin layer chromatography and, when the spot due to the starting material had disappeared, the mixture was poured into a mixture of 500 g of crushed ice and 50 ml of concentrated hydrochloric acid. It was then extracted with diethyl ether. The ethereal extract was dried over anhydrous sodium sulfate and the solvent was then distilled off. There were obtained 2.65 g (yield 96%) of the title compound in an impure form. To this material was added a small amount of benzene, and then hexane, yielding 1.28 g (yield 46%) of the title compound in the form of pure crystals, melting at 114.5°-117.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:21])=[N:17][N:18]2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(I)n[nH]c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(I)nn(C3CCCCO3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-3-iodo-1H-indazole (Preparation 16, 1.94 g, 4.9 mmol) in DCM (10 mL) was added p-TsOH (187 mg, 982 μmol) and the mixture was cooled to 0° C. 3,4-Dihydro-2H-pyran (660 μL, 7.4 mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5 mL) and washed with saturated sodium hydrogen carbonate aqueous solution (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to yield a black oil. The residue was purified by column chromatography (Biotage SNAP 10 g) eluting with a gradient of 20% EtOAc in heptane to give the title compound as a colourless oil (2.09 g) in an 89% yield.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([F:12])=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[OH-].[Na+]>ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=3)[CH2:11][CH:3]2[CH2:1][CH3:2])=[O:21])[CH:15]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: CCC1Cc2ccc(F)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g (10 mmol) 2-ethyl-6-fluoro-2,3-dihydro-1H-indol in 25 mL dichloromethane was added at 0° C. to 1.8 g (10 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 25 mL dichloromethane and then 10 mL (10 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The organic phase was separated off and evaporated down. The residue was purified on silica gel.
Reaction SMILES: C1(C[O:8][C@H:9]2[C@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: [H][H]
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C[C@H]1OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H]1CCNC[C@H]1O)c1ccccc1

Procedure:
A solution of 22.9 parts of trans-N-[3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinyl]benzamide in 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and suspended in trichloromethane. The whole was shaken with a dilute ammonium hydroxide solution and the layers were separated. The aqueous phase was evaporated and the solid residue was suspended in 5 parts of water. The product was filtered off and dried, yielding 6 parts of trans-N-(3-hydroxy-4-piperidinyl)benzamide; mp. 210° C. (compound 218).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)=[O:16])=[CH:12][N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)s1

Procedure:
2-[(tert-Butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid was coupled to benzyl 4-(aminomethyl)piperidine-1-carboxylate according to the procedure for EXAMPLE 1.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]
Reactant: CCOc1ncccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH:2]=1.B>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1
Reactant: O=C(O)CCCCCc1cccnc1
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCc1cccnc1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of 26.6 g of 3-pyridinehexanoic acid in 200 ml of dry tetrahydrofuran was cooled in an ice bath as 488 ml of 1 molar borane in tetrahydrofuran was added slowly. The reaction mixture was gradually brought to reflux temperature and was heated overnight. The excess reagent was quenched by the careful addition of 100 ml of methanol and the mixture was concentrated. The residue was diluted with excess 6N hydrochloric acid, allowed to stand overnight, made basic with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic layers were dried over potassium carbonate, and evaporated to an oil which was distilled to give 22.6 g (92%) of 6-(3-pyridyl)hexanol, bp 180°-200° C./0.2 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][N:12]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:11]#[N:12])[C:3]=2[CH:10]=[CH:9]1
Reactant: Brc1cncc2[nH]ccc12
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cncc2[nH]ccc12
Temperature: 100 °C
Yield: 85.1 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g, 5.08 mmol) in NMP (20 mL) under an argon atmosphere was added Zn(CN)2 (1.19 g, 10.15 mmol) and Pd(PPh3)4 (0) (590 mg, 0.51 mmol). The mixture was heated at 100° C. for 18 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (1:1) to afford 618 mg (85.1%) of 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile as yellow solid. MS (ESI): m/z=144.3 [M+1]+.