Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)C(C#N)[CH2:6][CH2:5]2.[CH3:14][C:15]([OH:17])=[O:16]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:14]([C:15]([OH:17])=[O:16])[CH2:6][CH2:5]2
Reactant: N#CC1CCc2cc(Cl)cc(Cl)c21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1CCc2cc(Cl)cc(Cl)c21
Temperature: 100 °C

Procedure:
A suspension of 5,7-dichloro-2,3-dihydro-1H-indene-1-carbonitrile (0.77 mmol) in 2 mL 25% HCl solution and 2 mL AcOH was heated to 100° C. for 5 h. At RT, the reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired compound as brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.Cl.[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:26][C:25]2[C:20]3[N:19]=[CH:18][N:17]([CH3:16])[C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: Cn1cnc2c(N)cccc21
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc2c1ncn2C
Yield: 61.5 %

Procedure:
A heavy walled resealable tube, was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.26 mmol) and 1-methyl-1H-benzo[d]imidazol-4-amine dihydrochloride (498 mg, 2.26 mmol) in acetonitrile (3.5 mL) with stirring. DIPEA (877 mg, 1.19 mL, 6.79 mmol) was added and the tube was heated with stirring in an oil bath at 80° C. for 24 h. Solvents evaporated and crude purified by flash chromatography (silica 20-45 μM, 80 g, Thomson, 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (461 mg, 1.39 mmol, 61%) as a light yellow solid. 1H NMR (CHLOROFORM-d) δ: 10.42 (s, 1H), 7.92 (s, 1H), 7.30-7.45 (m, 2H), 7.23-7.28 (m, 1H), 7.20 (s, 1H), 4.59 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 1.51 (t, J=7.2 Hz, 3H); LC-MS 332.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:14][C:15]1([CH3:21])[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH3:14][C:15]1([CH3:21])[CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=2)[C:17](=[O:20])[CH2:16]1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)nc1
Reactant: CC1(C)CNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N(c2ccc(C#C[Si](C)(C)C)cn2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
(260 mg, 1.0 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) was dissolved in toluene (2 ml) and 4,4-dimethylpyrrolidin-2-one (115 mg, 1.0 mmol, 1.0 equiv.), cesium carbonate (660 mg, 2.05 mmol, 2.0 equiv.), xantphos (CAS 161265-03-8) (24 mg, 0.04 mmol, 0.04 equiv.) and Pd2(dba)3 (19 mg, 0.02 mmol, 0.02 equiv.) were added under nitrogen. The mixture was stirred for 1 hour at 90° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (230 mg, 0.81 mmol, 75% yield) was obtained as a yellow solid, MS: m/e=287.1 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5](=[O:21])[O:4]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2>>[ClH:1].[CH3:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH:10]=2)[C:5](=[O:21])[O:4]1
Reactant: C[C@@H]1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1
Agent: C[C@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: Cl
Product: C[C@H]1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
(3S)-3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride was prepared in a similar manner as (3R)-3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride except starting from (3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [OH:1][C@@H:2]1[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[S:4][CH2:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CS(O)(=O)=O>[C:10]([O:1][C@@H:2]1[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[S:4][CH2:3]1)(=[O:12])[CH3:11]
Reactant: O=C(O)[C@@H]1O[C@@H](O)CS1
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Product: CC(=O)O[C@H]1CS[C@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (250 g, 1.67 mol) was added, in portions, to a stirred solution of acetic anhydride (0.625 L, 6.62 mol) and methanesulphonic acid (5 mL, 77 mmol) at room temperature. The resultant clear solution was stirred at room temperature for 60 minutes, slowly added to stirred aqueous 0.03M sodium bicarbonate solution (2.5L) and then the mixture was stirred for a further 60 minutes. Sodium chloride (750 g, 12.83 mol) was added and the mixture was stirred for a further 30 minutes, clarified, and then extracted with isopropyl acetate (1×1.25 L, 3×0.625 L). The combined extracts were concentrated to 1.25 L under reduced pressure. Xylene (2.5 L) was added and the mixture reconcentrated to 1.25 L under reduced pressure. The xylene addition/reconcentration procedure was repeated and the resultant suspension was cooled to room temperature and stirred for 18 hours. The solid was collected by vacuum filtration, washed with xylene (2×0.25 L) and dried, in vacuo, at 40°-45° to give the title compound (265 g, 83%) which was shown, by comparison of 1H NMR spectra, to be a 65:35 mixture of the compounds of Examples 3 and 4.
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17]([O:19][C:20](=[O:43])/[CH:21]=[CH:22]/[C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][N:24]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:18].C(O)(=O)C>C(O)C>[C:39]([O:38][C:36]([N:24]1[CH2:25][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH2:27][C@H:23]1[CH:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:43])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(C(C(=O)OCC)C(=O)OCC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To sodium metal (6.90 g, 0.30 mol), absolute ethanol (300 ml) was gradually added to prepare sodium ethoxide, and a solution of diethyl malonate (151.9 ml, 1.0 mol) in ethanol (500 ml) was dropwise added thereto at room temperature. A solution of (E)-3-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-acrylic acid ethyl ester (400 g, 1.0 mol, compound of Reference Example 1-4) in ethanol (1500 ml) was further added thereto at the same temperature, and stirred overnight. After acetic acid (17.2 ml, 0.30 mol) was added thereto under cooling with ice, the reaction solution was concentrated under reduced pressure to obtain triethyl 2-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-1,1,3-propanetricarboxylate (558.3 g) as a crude oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:9]=1[O:10][CH2:11][CH2:12][OH:13]>N1C=CC=CC=1>[S:2]([O:13][CH2:12][CH2:11][O:10][C:9]1[C:8]([O:7][CH3:6])=[CH:17][CH:16]=[CH:15][C:14]=1[O:18][CH3:19])(=[O:4])(=[O:3])[CH3:1]
Reactant: COc1cccc(OC)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1OCCOS(C)(=O)=O
Reaction time: 60 h
Yield: 40.5 %

Procedure:
Methanesulphonyl chloride (23 g.) was added dropwise to a stirred solution of 2-[2,6-dimethoxyphenoxy]ethanol (20 g.) (J. Med. Chem. 1969, 12, 326) in pyridine (50 ml.). The solution was left at room temperature for 60 hours, then the solvent evaporated under reduced pressure. The residue was taken up in chloroform, washed with water (3×100 ml.) and sodium bicarbonate solution (5%, 3×100 ml.), dried and the solvent evaporated. The residue was triturated with n-hexane and the solid collected to give 2-[2,6-dimethoxyphenoxy]-ethyl mesylate (11.3 g.) characterized spectroscopically.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=O)C>FC(F)(F)C(O)=O.ClCCl>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][C@@H:8]([C:28]([O:30][CH3:31])=[O:29])[NH2:7])=[O:12])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (Example 62; 200 mg, 0.45 mmol) in trifluoroacetic acid/dichloromethane (1:1; 2 mL) was stirred at room temperature for 40 min. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester. HOAT (73 mg, 0.45 mmol), DCC (111 mg, 0.45 mmol), 2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]-benzoic acid (Example 36; 148 mg, 0.45 mmol) and N,N-dimethylformamide (5 mL) were added and the solution was stirred at room temperature for 1.5 h. Water was added and the solution was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 40%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH2:2][CH3:3].Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH2:1]([NH:4][C:5]1[O:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:7]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CCCNC(N)=O
Product: CCCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 17.3 %

Procedure:
By the procedure of Example 4, 6.13 g (60 mmol) of n-propyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from n-heptane to yield 2.3 g of a yellow powder product (m.p.=33°-34° C.) identified in Table I.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:18][CH3:19])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16]C)=[O:14])[S:11][CH:12]=1)=[CH2:2]>CCO.[Pd]>[CH2:18]([N:6]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=2)=[C:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:19]
Reactant: C=Cc1cnn(CC)c1-c1csc(C(=O)OCC)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1cnn(CC)c1-c1csc(C(=O)OC)c1
Reaction time: 10 h
Yield: 98.9 %

Procedure:
Pd/C (12 mg, 10%) was added to a solution of ethyl 4-(4-ethenyl-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (150 mg, 0.57 mmol) in EtOH. The air in the system was removed by vacuum. The reaction mixture was stirred for 10 h under a balloon of hydrogen gas. The reaction was diluted with MeOH (2 mL) and filtered through Celite. Concentration of the reaction solution gave the title compound (149 mg, 94%) as a yellow oil: LC-MS (ES) m/z 265 (M+H)+.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl>[I:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:3])=[O:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1I
Solvent: ClCCl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The deprotected Rink amide polymer is suspended in 20 ml of DCM and 2.00 g (1.55 mmol, 2 equivalents) of DIEA, and then 1.93 g (6.18 mmol, 2 equivalents) of 2-iodo-5-nitrobenzoyl chloride (Example 2A) are added. The mixture is shaken at room temperature overnight. This is followed by washing three times each with DMF, methanol and DCM. The resulting polymer 1 is dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][NH:27][CH2:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:28]2)[N:3]=1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Reactant: COc1ccc2c(c1)CNCC2
Product: COc1ccc2c(c1)CN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)CC2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 7-methoxy-1,2,3,4-tetrahydroisoquinoline as the reagent of choice on the same molar basis as before. In this particular case, the final product was isolated as the hydrochloride salt m.p. 236° C.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=C(F)F)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1CCCCC1.C(Cl)Cl.CC(C)=[O:42]>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[O:42])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: CC(C)=O
Reactant: C[C@]12CCCCC1CC(=C(F)F)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3

Procedure:
Using the same reaction conditions described in Prepn. 31 and starting from 3,3:17,17-bis(ethylendioxy)androstane-7-one (Prepn. 42, 353 mg), 3,3:17,17-bis(ethylendioxy)-7-difluoromethyleneandrostane was obtained after flash chromatography (SiO2; cyclohexane:CH2Cl2:acetone 8:1:1) (115 mg, 30%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.85 (8H, m), 2.10-0.9 (20H, m), 0.96 (3H, s), 0.83 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CC3)C(=O)N2
Yield: 33 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxy-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetra hydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].[C:48](Cl)(=[O:52])[O:49][CH2:50][CH3:51]>O1CCCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:48]([O:49][CH2:50][CH3:51])=[O:52])[N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCNCC3)cc2NC2CCOCC2)c2cc(Cc3cc(F)cc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate (0.013 mmol) in anhydrous tetrahydrofurane (1.0 mL) maintained at −50° C. under argon atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.015 mL) was added. After stirring at that temperature for 5 minutes ethyl chlorocarbonate (0.002 mL, 1.63 mg, 0.015 mmol) was added. After 30 minutes at −50° C. the reaction was completed. After diluting with dichloromethane, the solution was washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added and the mixture was stirred at room temperature overnight. After diluting with dichloromethane, the solution was washed with sodium hydrogencarbonate, with brine, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:16]4[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])=[CH:18][C:17]=4[F:34])[C:14]=3[F:15])[CH:11]=2)[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:16]4[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:36])[CH3:23])=[CH:18][C:17]=4[F:34])[C:14]=3[F:15])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-c2nn3cc(OCC4CC4)ccc3c2F)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nn3cc(OCC4CC4)ccc3c2F)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-3-fluoropyrazolo[1,5-a]pyridin-2-yl]-3-fluorophenoxy}-1-methylethyl]carbamate (67 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (1 mL) was stirred at room temperature for 6 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (1 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.4 mg) as white crystals.
Reaction SMILES: O.Cl.[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1>CO.[O-2].[O-2].[Mn+4]>[CH:4]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1)=[O:3]
Reactant: CNC(=O)c1cc(CO)ccn1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: CO
Solvent: O
Product: CNC(=O)c1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.50 g (33.989 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide hydrochloride hydrate (Example 40A) were initially charged in 90 ml of methanol, 23.64 g (271.915 mmol) of manganese dioxide were added and the mixture was stirred at RT overnight. The reaction mixture was filtered off with suction through silica gel, the silica gel/manganese dioxide mixture was stirred with tetrahydrofuran/methanol 1:1 overnight, the silica gel/manganese dioxide mixture was then filtered off and the filtrate was evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>CS(C)=O.O.O1CCCC1>[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:31])=[CH:7][N:6]=1
Reactant: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
Combine (±)-6-[2-methyl-4-(3-phenyl-piperidinylmethyl)-phenoxy]-nicotinonitrile (compound of example 365, step 2) (0.878 g, 2.29 mmol) and potassium carbonate (0.159 g, 1.15 mmol) in dimethylsulfoxide (11.0 mL,). Treat the mixture with 30% hydrogen peroxide solution (aq) (0.77 mL, 6.79 mmol), and stir at ambient temperature. After 4 h, dilute the reaction mixture with water (25 mL) and extract with ethyl acetate (3×30 mL). Wash combined ethyl acetate extracts with brine, dry over anhydrous magnesium sulfate, filter, and concentrate. Crude product is pure by 1H NMR and reverse-phase HPLC. Dissolve product in tetrahydrofuran (12 mL) and treat with methanesulfonic acid (0.148 mL, 2.28 mmol). White precipitate forms and turns oily within 3 minutes. Dissolve residue in tetrahydrofuran and concentrate. Product purity is 82% by reverse-phase HPLC. Purify residue by reverse-phase HPLC. Concentrate fractions containing pure product, recrystallize from methanol:diethyl ether (2:5, 16 mL), and isolate product by vacuum filtration to provide 0.0941 g (10%) of the title compound as white/tan crystals: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.62 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.57-7.54 (m, 1H), 7.48 (dd, 1H, J=1.5, 7.8 Hz), 7.43-7.38 (m, 2H), 7.37-7.30 (m, 3H), 7.23 (d, 1H, J=8.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 4.45-4.36 (m, 2H), 3.63 (t, 2H, J=14.6 Hz), 3.22 (t, 1H, J=12.2 Hz), 3.17-3.07 (m, 2H), 2.23 (s, 3H), 2.20-2.13 (m, 1H), 2.12-2.92 (m, 2H), 1.86 (dq, 1H, J=3.9, 12.2 Hz).