Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([C:10]2[NH:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][CH:15]([C:13]1[N:14]=[C:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:11][CH:12]=1)[OH:16]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl magnesium bromide (15.3 ml., 2.5 molar in ether) is added dropwise to a solution of 2-phenyl-4-imidazolecarboxaldehyde (3.0 gm. 0.017 mole) in dry tetrahydrofuran (45 ml.; dried over a molecular sieve) while the temperature of the reaction mixture is maintained with cooling at 25° C. The mixture is stirred for 2 hours, and then decomposed by adding a large volume of water dropwise. The mixture is extracted with ether (3×75 ml.), the ethereal extract is partially evaporated to yield a white precipitate, the crystalline alcohol, m.p. 197°-198° C.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[CH2:17][C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39].CCCCCC.C(COC)[O:47]C>>[CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[C@H:17]([OH:47])[C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39]
Reactant: COCCOC
Reactant: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)C[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(/C)[C@H](O)[C@@H](C)/C=C\C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)C[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Solvent: CCCCCC
Product: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@H](O)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2

Procedure:
0.2 g of milbemycin A4 is added to a 2-day-old preculture of S. violascens produced according to H1 in 450 ml of medium 2, and the whole is shaken at 250 rpm. at 28° C. The course of the reaction is monitored by means of HPLC (high pressure liquid chromatography) (column 25 cm/0.5 cm, eluant hexane/dimethoxyethane 3:1, 1 ml/min., UV detector 220 nm). After shaking for 4 days and a 37% conversion rate, 70% 13β-hydroxymilbemycin A4 and 30% 14,15-epoxymilbemycin A4 are obtained.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.[NH2:56][C:57]1[C:62](C#N)=C(Cl)[N:60]=[CH:59][N:58]=1.ClC1N=CN=C(N)C=1>>[NH2:56][C:57]1[N:58]=[CH:59][N:60]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[CH:62]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: Nc1cc(Cl)ncn1
Product: Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 145 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloropyrimidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.00 (d, J=7.28 Hz, 1H), 7.50 (br. s., 2H), 6.54-6.70 (m, 1H), 6.47 (d, J=1.76 Hz, 3H), 3.98 (br. s., 1H), 3.84 (br. s., 1H), 3.55-3.71 (m, 6H), 3.06 (dd, J=8.91, 12.93 Hz, 2H), 1.76 (br. s., 3H), 1.38-1.60 (m, 3H). EIMS (m/z): calcd. for C17H20Cl2N6O (M+1H) 395. found 395.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH:18]([CH3:21])[CH2:17][C:16](=[O:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25][CH3:26])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(C)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1ccccc1
Yield: 20.9 %

Procedure:
A solution of the 9-[(phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.30 g, 3.74 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.93 g, 4.12 mM) in 37 mL of toluene was stirred between 80-90° C. for 5 hours. The mixture was purified by column chromatography on silica gel (elution with methylene chloride) to afford 270 mg (21%) of the 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ 10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3 (m, 3H), 7.05 (m, 2H), 6.65 (s, 1H), 6.6 (s, 1H), 5.5 (s, 2H), 4.1 (s, 3H), 2.45 (s, 3H). MS (ES) m/e 314, 346.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[NH2:17][NH2:18]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Solvent: CC(=O)N(C)C
Product: Cc1nc(-n2c(C)ccc2C)nc(NN)c1Br
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (4.95 g, 16.5 mmol) and hydrazine (0.57 ml, 18.1 mmol) hunig's base 95.74 ml, 32.9 mmol) and dimethyacetamide (24 ml) at R.T. After heating in the microwave for 30 mins at 100° C. The reaction mixture was concentrated under reduced pressure to dryness and the residue was trituarated with 1:1 ethyl acetate:methanol to obtain the desired product as a white solid weighted 2820 mg. The mother liquor was purified by column chromatography eluted with 30% EtOAc:hexane to give an additional batch of the desired product. Both lots were combined to give the titled compound as a white solid weighted 3620 mg 74%
Reaction SMILES: [CH3:1][C@H:2]1[CH2:23][C@@H:22]2[C@:17]([CH3:25])([CH:18]=[CH:19][C:20](=[O:24])[NH:21]2)[C@@H:16]2[C@@H:3]1[C@H:4]1[C@:13]([CH3:26])([CH2:14][CH2:15]2)[C@@H:7]([C@:8]([CH2:11][CH3:12])([OH:10])[CH3:9])[CH2:6][CH2:5]1.[CH3:27]I.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[CH3:27][N:21]1[C:20](=[O:24])[CH:19]=[CH:18][C@@:17]2([CH3:25])[C@H:22]1[CH2:23][C@H:2]([CH3:1])[C@@H:3]1[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:26])[C@H:4]1[CH2:5][CH2:6][C@@H:7]2[C@:8]([CH2:11][CH3:12])([OH:10])[CH3:9]
Reactant: CC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4N(C)C(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
A solution of 46 mg (0.128 mmol) of 7β-methyl-20-ethyl-20(S)-hydroxy-5α-4-azapregn-1-en-3-one (from Example 6) in 5 ml dry dimethylformamide was cooled to 0° C. under N2. Methyl iodide (10 eq, 1.3 mmol) and sodium hydride (2 eq, 25 mmol) were added and the reaction was stirred at RT for 24 hours. Aqueous ammonium chloride was added and the reaction mixture was poured onto 100 ml water and extracted with three 25 ml portions of ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, and evaporated. The product was purified by silica gel MPLC using 10% acetone/methylene chloride to yield 30 mg (0.08 mmol, 63% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21](=[O:36])[NH:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[H-].[Na+].[CH3:40]I.O>CN(C)C=O>[Cl:1][C:2]1[C:20]([C:21](=[O:36])[N:22]([CH3:40])[CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)NCCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N(C)CCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (390 mg) in N,N-dimethylformamide (4 ml) was added sodium hydride (32.1 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. Methyl iodide (114 mg) was added thereto under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform:ethyl acetate=3:1, V/V) to give 8-(2,6-dichloro-3-[N-methyl-N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (360 mg) as colorless amorphous.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]#[N:7].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)c(O)c1
Reaction time: 6 h
Yield: 66.2 %

Procedure:
3-Methoxy-4-phenylbenzonitrile (17.8 g) was dissolved in dichloromethane (200 mL). To the stirred mixture was added dropwise boron tribromide (14 mL) under ice-cooling, and the mixture was stirred at continuous temperature for 6 hours. To the stirred reaction mixture was added dropwise water (200 mL) under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (11.0 g).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O.C([O-])(=O)C.[K+].O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12][CH:13]([CH3:14])[CH3:15])[C:9]([Cl:16])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)Sc1cc(S(N)(=O)=O)c(N)cc1Cl
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Sc1cc2c(cc1Cl)N=C(CCl)NS2(=O)=O

Procedure:
A mixture of 2-sulfamoyl-4-isopropylthio-5-chloroaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in dioxane (75 ml.) is heated under reflux for 24 hours. The solution then is concentrated to dryness in vacuo, the residue dissolved in ethanol (60 ml.) and heated under reflux with potassium acetate (0.022 mole) and water (10 ml.) for 2 hours. The alcohol is removed in vacuo and the solution then acidified with hydrochloric acid. The precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 248°-250° C.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[C:19]([CH:20]=[O:21])=[CH:18][C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([F:22])[CH:16]=3)[N:11]=2)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+].O>C(O)C>[CH:1]1([CH2:6][N:7]([C:10]2[C:19]([CH2:20][OH:21])=[CH:18][C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([F:22])[CH:16]=3)[N:11]=2)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC1CCCC1)c1nc2cc(F)c(F)cc2cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCN(CC1CCCC1)c1nc2cc(F)c(F)cc2cc1CO
Reaction time: 2 h

Procedure:
To a mixture of 2-[N-(cyclopentylmethyl)-N-ethylamino]-6,7-difluoroquinoline-3-carbaldehyde (0.10 g, 0.31 mmol) in ethanol (2.0 mL) is added sodium borohydride (14 mg, 0.37 mmol) and the mixture is stirred for 2 hours. After addition of sat. ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to {2-[N-(cyclopentylmethyl)-N-ethylamino]-6,7-difluoroquinolin-3-yl}methanol which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(C)NC(=O)CCl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Cn1c2c(c3cc(Cl)ccc31)CCN(C)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) was added to the solution and stirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (65 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then the residue was extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([N:8]=[C:9](OCC)[CH2:10][C:11]#[N:12])#[N:7]>O1CCCC1>[C:6]([N:8]=[C:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][C:11]#[N:12])#[N:7]
Reactant: C1CCNC1
Reactant: CCOC(CC#N)=NC#N
Solvent: C1CCOC1
Product: N#CCC(=NC#N)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyrrolidine (2.07 g, 0.0292 m) is added to 4.00 g (0.0292 m) of an ice-cooled solution of ethyl N,2-dicyanoacetimidate in 80 ml of tetrahydrofuran and stirred for two hours at room temperature. The crude product is isolated and chromatographed in the same manner as that of Example 2. The tlc-pure crystalline product (4.80 g) is triturated with diethyl ether to give 4.00 g (84%), mp 45° C. Nmr and ir are consistent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[N:3]=1.C(N(CC)CC)C.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:20]([CH2:19][N:3]1[C:2]([CH3:1])=[C:7]([Br:8])[C:6]([CH3:9])=[N:5][C:4]1=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(=O)[nH]c(C)c1Br
Reactant: ClCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(=O)n(COc2ccccc2)c(C)c1Br
Temperature: 40 °C

Procedure:
A mixture of 4,6-dimethyl-5-bromopyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (60 ml) was heated at 40° C. for dissolution. The solution was then cooled to room temperature and (chloromethoxy)benzene [see Preparation 2] (4.7 mmol) in dichloromethane (15 ml) was added. The resultant mixture was stirred at room temperature for 11/2 h, the solvent distilled off, the mixture triturated with water, the remaining solid extracted with chloroform, the dried (MgSO4) chloroform solution evaporated, the residue triturated with a little ether, the residue redissolved in chloroform and the solution chromatographed on a column of alumina, activity III, using chloroform, Yield 0,35 g (24%), m.p. 120° C. (CCl4) (Found C50.32; H4.15. Calc. for C13H13BrN2O2 : C50.50; H4.25) 1H NMR (CDCl3): δ 2.50 and 2.68 (4-Me and 6-Me), 6.03 (CH2), 6.8-7.4 (Ph), MS [70 eV, m/z (% rel. int)]. 310/308 (6/7,M), 217(97), 215(100), 174(15), 172(12), 136(20), 135(19), 108(23) 94(19).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[C:8]([C:15](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:31])[CH:3]=1.[NH3:32]>C1COCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[C:8]([C:15]([NH2:32])=[O:16])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:31])[CH:3]=1
Reactant: N
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(Br)cc2F)cc1=O
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 100 %

Procedure:
2,3,4,5,6-Pentafluorophenyl 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF was reacted with conc. NH3 solution as for example 37, step B. Recrystallisation (EtOAc/Hexane) yielded 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (100%); m.p. (EtOAc/Hexane) 282-284° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.39 (s, 1H), 8.35 (s, 1H), 7.89 (br s, 1H), 7.66 (dd, J=10.4, 1.7 Hz, 1H), 7.51-7.44 (br m, 2H), 7.42 (dd, J=8.5, 1.9 Hz, 1H), 5.55 (s, 1H), 3.38 (s, 3H). LCMS (ACPI−) 340 (100%), 338 (90%). Anal. Calcd for C13H11BrFN3O2: C, 45.9; H, 3.3; N, 12.4. Found C, 46.1; H, 3.2; N, 12.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][OH:35])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][OH:35])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCO)c(NS(C)(=O)=O)c3)cc12
Yield: 13.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxyethoxyl)phenyl) methanesulfonamide (150 mg, 0.208 mmol) was hydrolyzed by lithium hydroxide (88 mg, 2.08 mmol), THF/Methanol/water (3/3/1.5 ml) to afford 15 mg (15.38% yield) of the title compound. 1H NMR (DMSO-d6, 300 MHz): δ11.9 (s, 1H), 9.00 (s, 1H), 8.49 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.51-7.41 (m, 3H), 7.15-7.12 (d, 1H), 7.05-7.03 (m, 1H), 6.87 (s, 1H), 4.06 (m, 2H), 3.78 (m, 2H), 3.00 (s, 3H), 2.18-2.14 (d, 6H), MS: m/z=550.1 (M+1), HPLC: 87.11% in Method B.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:10][CH:9]=1)=[O:7].I[CH3:32]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH3:32])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:12][CH:13]=1)=[O:7]
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4Cl)cc3)c2)o1

Procedure:
N-(2-Chlorobenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(2-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77,(1H, b), 7.62-7.33,(9H, m), 4.78-4.62,(2H, m), 2.95,(3H, s), 2.56,(3H, s), 2.33-2.29,(3H, m). LCMS; retention time 3.54 min, MH+ 432/434.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9]>C1(C)C=CC=CC=1>[O:11]=[C:10]([CH3:12])[CH2:8][CH2:9][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1
Reactant: C=CC(C)=O
Reactant: Oc1cc(Cl)sn1
Solvent: Cc1ccccc1
Product: CC(=O)CCn1sc(Cl)cc1=O

Procedure:
A solution of 0.5 g (0.0037 mole) of 5-chloro-3-hydroxyisothiazole and methyl vinyl ketone (1.0 g, 0.014 mole) in 15 ml of toluene was heated at 80° C. for 24 hours. After cooling and removal of toluene and excess reagent by rotary evaporation, the residual oil was purified by column chromatography on silica gel, using diethyl ether/methanol (9/1) as eluant. Compound 1 was obtained as an oil; 0.65 g (85%); IR (neat) 1725,1650 cm-1 ; NMR (CDCl3) δ6.25 (s,1H); 4.0 (t,2H); 2.9 (t,2H); 2.2 (s,3H).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (965 mg, 6.722 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.720 g, 8.066 mmol), DIPEA (955.6 mg, 1.288 mL, 7.394 mmol) and crushed 4A MS (965 mg) in DCE (30 mL) were stirred at ambient temperature for 3 hours. NaBH(OAc)3 (2.848 g, 13.44 mmol) was added and the reaction stirred at ambient temperature for a further 16 hours. The mixture was filter through Celite (washing with DCM) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a colourless oil that was used directly into next step without further purification. LC-MS ES+: 305.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:11]=[C:10]([C:20]([O:22]C)=[O:21])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c2c1CCc1cc(Cl)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn(-c2ccccc2)c2c1CCc1cc(Cl)ccc1-2
Reaction time: 3 h

Procedure:
A mixture of 15 parts of methyl 7-chloro-1-phenyl-4,5-dihydro-1H-benz[g]indazole-3-carboxylate, 100 parts of aqueous 10 percent sodium hydroxide solution and 120 parts of methanol is refluxed and stirred for 3 hours. The mixture is then cooled and acidified with concentrated hydrochloric acid. The solid which forms is separated by filtration, washed with water, and dried to give 7-chloro-1-phenyl-4,5-dihydro-1H-benz[g]indazole-3-carboxylic acid melting at about 282°C. with evolution of gas.