Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:6]([CH3:8])=O)[C:3]([NH2:5])=[O:4].CC(C(C)=O)C(OCC)=O.[OH-].[NH4+].[C:21]([CH2:23][C:24]([O:26]CC)=O)#[N:22]>>[NH4+:5].[OH:26][C:24]1[C:23]([C:21]#[N:22])=[C:6]([CH3:8])[C:2]([CH3:1])=[C:3]([OH:4])[N:5]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)C(C)C(N)=O
Agent: CCOC(=O)C(C)C(C)=O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(O)nc(O)c(C#N)c1C
Yield: 90 %

Procedure:
2-methylacetoacetamide 2, made from ethyl 2-methylacetoacetate 1 by reaction with ammonium hydroxide for six days (at about 60% yield), is reacted with ethyl cyanoacetate 4 over four days to produce 2,6-dihydroxy-4,5-dimethyl-3-pyridinecarbonitrile, ammonium salt 5 (90% yield). The ammonium salt is hydrolyzed with hydrobromic acid and decarboxylated. The excess hydrobromic acid is evaporated to dryness followed by filtration of ammonium bromide after taking up the 2,6-dihydroxy-3,4-dimethylpyridine hydrobromide salt 6 in absolute ethyl alcohol. The ethyl alcohol is evaporated to dryness and the residue is heated with water and potassium hydroxide to isolate 2,6-dihydroxy-3,4-dimethylpyridine (70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 80 °C

Procedure:
To a mechanically stirred suspension of 2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1 L toluene was added diisopropyl ethylamine (100 mL), followed by phosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was distilled under reduced pressure to remove toluene, and the resulting residue was dissolved in 2.2 L CH2Cl2. Ice water was added, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution while maintaining the temperature below 20° C. The resulting organic layer was separated and the aqueous solution extracted with CH2Cl2, then the combined the organic layers were dried over sodium sulfate and distilled under reduced pressure. The crude product was dissolved 2:1 CH2Cl2/hexane, and the solution was passed through silica gel (2.5 kg, 60-120 mesh), followed by washing the silica bed with 2:1 CH2Cl2/hexane until the product eluted. The pure fractions were collected and combined, and the solvent was removed under reduced pressure. Hexane (500 mL) was added, and the mixture was stirred and filtered to give 4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white to off-white solid (77 g, 72%). mp 161-164° C. 1H NMR (CDCl3) δ 2.6 (s, 3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2 (d, 1H) ppm; M/z (obs., [m+H]+)=285.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[S:11]([O-])([O-:13])=[O:12].[Na+].[Na+]>ClS(O)(=O)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A solution of 1-chloro-4-nitrobenzene (476 g, 3.02 mol) in chlorosulfonic acid (1 litre) was stirred and heated at 120° C. for 22 hours. The reaction was cooled to room temperature and was poured slowly with stirring onto ice (10 litres). The resulting dark brown precipitate was filtered, pressed dry, dried in a vacuum desiccators over night and was used without any further purification (770 g). The resulting 2-chloro-5-nitro-benzenesulfonyl chloride was suspended in water and cooled to 0° C. (ice bath). Sodium sulphite (1.9 Kg, 15 mol) was added to the stirred solution by portion (100 g portion and in a manner that the temperature remains under 25° C.). After the addition the mixture was allowed to warm back to room temperature and left stirring for one hour. During that time the pH of the solution was kept at pH 7-8 (Whattman pH paper) by addition of 8 M solution of sodium hydroxide (400 ml). The solution was then diluted with water (6 L) and sodium hydroxide was added to it (8 M, 0.5 L). The resulting mixture was filtered through a sintered funnel (number 3). The filtrate was cooled to 0° C. (ice bath) and acidify with concentrated HCl to pH<1. The brown solution then turn green and a silvery green plates precipitate. The solid was filtered, pressed dry and dried in a vacuum desiccator to give the title compound (213 g, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])[CH2:19][OH:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: N[C@H](CO)c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (750 mg, 3.30 mmol), (2S)-2-amino-2-(3-chloro-2-fluorophenyl)ethan-1-ol (746 mg, 3.30 mmol) and HBTU (1.75 g, 4.62 mmol) in CH2Cl2 (30 mL) was added under nitrogen DIPEA (2.31 mL, 13.20 mmol). The reaction mixture was stirred at RT overnight. CH2Cl2 and water were added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give the desired compound as a colorless oil. MS (UPLC/MS): 399.3/401.3 [M+H]+, 443.4/445.3 [M+HCOO]−; tR (HPLC conditions a): 3.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](OCC)=[O:10])[CH:6]=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)c1ccnc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 5 mmol) in ether (5 ml) was added to lithium aluminium hydride (0.3 g, 8 mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methoxypyridine (0.64 g, 89%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11]1[CH2:15]CC[CH2:12]1.CN(C)C=O.COCCl>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:12][O:11][CH3:15])=[CH:8][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 2.32 g) was added portion wise to a solution of 6-Chloro-pyridin-3-ol (5.00 g, 38.6 mmol) in a mixture of Tetrahydrofuran (10.0 mL, 123 mmol) and N,N-Dimethylformamide (20.0 mL, 258 mmol). The mixture formed was stirred for 15 min and Chloromethyl Methyl Ether (3.66 mL, 48.2 mmol) was added dropwise. The above mixture was stirred for 6 hours (monitored by LCMS), poured into water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum. Purified on 40 g silica column eluting with 10-40% ethyl acetate in heptane to give 6.33 g of 2-chloro-5-(methoxymethoxy)pyridine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.[CH2:8]=[O:9]>>[CH3:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[C:5]1[CH2:8][OH:9]
Reactant: C=O
Reactant: Cc1nncn1C
Product: Cc1nnc(CO)n1C
Temperature: 90 °C
Yield: 82 %

Procedure:
A mixture of 3,4-dimethyl-4H-1,2,4-triazole (2.3 g, 23.7 mmol) and formalin (5 mL) was heated to 90° C. overnight. The mixture was concentrated to give crude product. The crude product was purified by silica gel chromatography (dichloromethane/methanol=200:1 to 15:1) to give the title compound (2.48 g, yield 82%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 2.31 (s, 3H), 3.52 (s, 3H), 4.52-4.54 (d, J=5.2 Hz, 2H), 5.49-5.51 (t, J=5.2 Hz, 1H). LC-MS (ESI) m/z: 128 (M+1)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[C:11]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)cnc1Br
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Nc2cnc(Br)c(C)c2)c(C(=O)O)c1
Yield: 20 %

Procedure:
Obtained (0.51 g, yield 20%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (7.70 mmol, 1.44 g) and 2-chloro-5-methylbenzoic acid (15.36 mmol, 2.62 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N:33]5[CH2:38][CH2:37][CH:36]([CH2:39]OS(C)(=O)=O)[CH2:35][CH2:34]5)=[N:31][N:32]=4)[CH:29]=3)[CH2:15][CH2:14]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][NH:47][CH3:48]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C@@H:13]2[C:22]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:16]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N:33]5[CH2:34][CH2:35][CH:36]([CH2:39][N:47]([CH3:48])[CH3:46])[CH2:37][CH2:38]5)=[N:31][N:32]=4)[CH:29]=3)[CH2:15][CH2:14]2)=[O:45])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(COS(C)(=O)=O)CC5)n4c3)c3ccccc32)no1
Reactant: CNC
Product: CN(C)CC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)on5)c5ccccc54)cn23)CC1

Procedure:
Intermediate 15c was reacted with dimethylamine in an analogous manner to that described in Example 14 step i to give the title compound. LCMS (Method 5): Rt: 3.30 min, m/z 587.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.33-1.47 (2H, m), 1.64-1.75 (1H, m), 1.75-1.84 (2H, m), 1.85-2.11 (4H, m), 2.13-2.20 (8H, m), 2.85-2.99 (2H, m), 3.35-3.47 (2H, m, obscured by water), 4.86-4.94 (1H, m), 5.56 (1H, t, J=4.5 Hz), 6.41 (1H, s), 7.01 (1H, d, J=8.4 Hz), 7.20 (1H, dd, J=9.8, 2.2 Hz), 7.27-7.34 (1H, m), 7.35-7.43 (3H, m), 7.62 (1H, d, J=10.2 Hz), 7.65 (1H, d, J=1.7 Hz), 8.20 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24](I)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39]C.C[Si](C#C)(C)C>C(OCC)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([C:38]#[CH:39])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Reactant: CCCN
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CCOCC
Product: C#Cc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 95 °C

Procedure:
To a suspension of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo- 1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 4.2 Step B, 200 mg in 3 mL N,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium (18 mg) followed by copper(I) iodide (30 mg), n-propylamine (0.26 mL) and trimethylsilylacetylene (0.45 mL) and the mixture sealed in a thick-walled tube. This was heated to 95° C. on an oil bath for 10 hours, then cooled to room temperature and diluted with diethyl ether. This was washed successively with water and brine and the combined organics dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60) gave a mixture of the title compound and the corresponding trimethylsilyl derivative (155 mg). This material was converted to the title compound by treatment with 4.4 mg of potassium carbonate in 2 mL methanol. After 1 hour, the mixture was diluted with methylene chloride, washed with half-saturated sodium chloride, then brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60) gave the title compound (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][OH:25])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(4-methoxycarbonylbutyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (409.7 mg).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH3:1][CH:2]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:40])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=1)[CH2:3][C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CC#N)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg (0.37 mmol) of the compound from Example 54 were introduced into 20 ml of dichloromethane at 0° C., 92 mg (0.37 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 150 mg (96% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH3:8].O.C([OH:14])C.Cl>C(OC(=O)C)(=O)C>[Br:1][C:2]1[C:3]([CH2:10][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc[n+]([O-])c(C)c1Br
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(CO)c1Br

Procedure:
3-Bromo-2,4-dimethylpyridine-N-oxide (14.7 g) in warm acetic anhydride (150 ml) was added dropwise to acetic anhydride (500 ml) at 125° and the mixture was refluxed for 1/2 hour, allowed to cool and then poured into water/ethanol (4:1, 500 ml). The solution was acidified with dilute hydrochloric acid and evaporated to dryness. The residue was refluxed with 2 N hydrochloric acid (100 ml) for 1 hour, cooled and extracted with chloroform. The aqueous phase was adjusted to pH 12 with sodium hydroxide and was extracted with chloroform, and this chloroform extract was evaporated to a residue which was crystallised from n-hexane to give 3-bromo-2-hydroxymethyl-4-methylpyridine (5.8 g) m.p. 75°-77°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47 %

Procedure:
Using the general method of Example 150 except that the reaction was run at 0° C., 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) was reacted with 4-morpholinecarbonyl chloride (1.17 g, 7.8 mmol) to provide 1.35 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 226.0-228.0° C. Analysis: Calculated for C19H24N6O2: %C, 61.94; %H, 6.57; %N, 22.81; Found: %C, 61.67; %H, 6.46; %N, 22.74.
Reaction SMILES: [CH3:1]/[C:2](/N)=[CH:3]\[C:4]#[N:5].Cl.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][NH2:16].[OH-].[Na+]>Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:5])[N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:8])[N:16]=1
Reactant: C/C(N)=C\C#N
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N)n(-c2ccccc2C)n1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
3-Aminocrotonitrile (2.00 g, 24.4 mmol) was added to a stirred solution of (2-methylphenyl)hydrazine hydrochloride (3.67 g, 23.1 mmol) in 1 M hydrochloric acid (20 mL). The reaction was heated (100° C.) for 18 h and then cooled to rt. The solution was adjusted to pH>12 using 1 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×20 mL), and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 25-50% ethyl acetate/hexane afforded 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (3.97 g, 87%) as an orange oil. 1H NMR (300 MHz, acetone-d6) δ 7.29 (m, 4H), 5.32 (s, 1H), 2.12 (s, 3H), 2.08 (s, 3H); ES-MS m/z 188.2 (MH+), HPLC RT (min) 0.79.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nn1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Yield: 64.7 %

Procedure:
Using 6-chloropyridazine-3-carboxylic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.37 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.46 g) was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C13H17N3O2 m/z 308 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]1([C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:22][CH2:23]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: CCOC(=O)COCCCl
Product: CCOC(=O)COCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
This ester is prepared by the method described in Example 1.2, starting from ethyl (2-chloroethoxy)-acetate and 4-(diphenylmethylene)-piperidine. It is not isolated but used as such, without further purification, for the preparation of the corresponding acid (see Example 3.3).