Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: Cc1ncc(Br)n1C
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ncc(C(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-1,2-dimethyl-1H-imidazole (10.0 g, 57.1 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 19.0 mL, 57.0 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-Methoxy-N-methyl-benzamide (8.70 mL, 57.1 mmol) was added dropwise. The mixture was stirred for 7.5 h at room temperature. The mixture was worked-up by addition of water (100 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (2×75 mL), the organic layers were washed with water (2×100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methanone [8.41 g, yield 44%; HPLC/MS: m/z=201 (M+H); log P(HCOOH)=0.56].
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=1.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)=[N:4]2)=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(-c2nn[nH]n2)c(N)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nnn(Cc3ccc(OCc4ccccc4)cc3)n2)c(N)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
3-(2H-tetrazol-5-yl)-pyridin-2,6-diamine (60 mg) described in Manufacturing Example 7-3, 4-benzyloxybenzyl chloride (79 mg), sodium iodide (51 mg), NaH (14 mg, 60% in oil), and DMF (0.69 mL) were stirred for 10 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1, then ethyl acetate). Ethyl acetate-hexane was added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (26 mg).
Reaction SMILES: F[C:2]1[C:23]([C:24]2[NH:28][C:27]([CH3:29])=[N:26][N:25]=2)=[CH:22][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:30])[CH:3]=1.CC1NC(C2C=C(C=CC=2F)C([N:43]2[CH2:48][CH2:47][CH:46](C3C=CC(C#N)=CC=3)[CH2:45][CH2:44]2)=O)=C(C)N=1.N1CCCCC1>>[CH3:30][C:4]1[CH:3]=[C:2]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:23]([C:24]2[NH:28][C:27]([CH3:29])=[N:26][N:25]=2)=[CH:22][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Solvent: C1CCNCC1
Product: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2N2CCCCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 25, except 4-(1-(4-fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 101.4) was used in place of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1) and piperidine was used in place of azetidine hydrochloride. m/z (ES+) 469 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([CH2:45][O:46][NH2:47])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([CH2:45][O:46][N:47]=[CH:1][C:3]2[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=2)[CH2:6][N:7]([C@@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[C:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[O:9])=[CH:48][CH:49]=1)([O-:40])=[O:39]
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3ccc([N+](=O)[O-])cc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-(4-nitrobenzyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:6]=1.[OH-].[Na+]>CO>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:23])=[O:2])=[CH:6]1
Reactant: COC(=O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]acetic acid methyl ester (23 mg, 0.066 mmol) in MeOH (0.5 mL), is added 4N NaOH (0.25 mL). The reaction mixture is stirred at 25° C. for 5 minutes. The reaction mixture is evaporated in vacuo, to remove MeOH then cooled in an ice bath and acidified with concentrated HCl. The resultant solid is collected by filtration and triturated in CHCl3 to afford [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-y]-acetic acid; MH+=335.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1C.O.[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>N1C=CC=CC=1>[C:10]([NH:9][C:5]1[N:6]=[C:7]([C:14]([OH:15])=[O:17])[C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(Br)c(C)n1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)n1
Temperature: 90 °C
Yield: 603.8 %

Procedure:
To a solution of N-(5-bromo-6-methyl-pyridin-2-yl)-acetamide 48.46 g in pyridine 250 ml was added water 250 ml and the mixture warmed to 90° C. and potassium carbonate 2.2 g was added. Potassium permanganate was added portionwise over 10 h and the mixture allowed to cool slowly overnight. The reaction mixture was re-heated to 90° C. for 2 h, cooled slightly and filtered to remove manganese dioxide. The filtrate was evaporated in vacuo and the residue partitioned between water 1 L and ethyl acetate 500 ml. The aqueous solution was washed with ethyl acetate. The organic solutions were combined, washed with brine, dried MgSO4 and evaporated in vacuo to recover unchanged starting materials 12.6 g. The aqueous solution was acidified with concentrated hydrochloric acid (circa 80 ml) and the solid product filtered off, washed with a minimum of water, sucked dry and then dried at 80° C. (vac) to give 6-acetylamino-3-bromo-pyridine-2-carboxylic acid 24.9 g
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[CH2:9]([C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:10]
Reactant: CCc1cc(Br)ccc1N
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCc1cc(-c2cnn(C)c2)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 98 using 4-bromo-2-ethylaniline and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:18]([NH2:20])[CH3:19])=[C:10]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[CH:11]=2)[CH:6]=[CH:5]1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[C:24]([S:31][CH3:32])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]=[C:7]3[CH:6]=[CH:5][N:4]([CH3:3])[C:12]3=[CH:11][C:10]=2[C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH3:19])[N:25]=[C:24]([S:31][CH3:32])[N:23]=1
Reactant: CSc1nc(N)c(C#N)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1cscn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2cscn2)n1
Temperature: 120 °C
Yield: 8.6 %

Procedure:
(S)-1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine dihydrochloride (200 mg, 0.604 mmol), 4-amino-6-chloro-2-(methylthio)pyrimidine-5-carbonitrile (182 mg, 0.906 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.315 mL, 1.81 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by column chromatography eluting with 20-80% EtOAc in hexane over 60 minutes. The fractions containing the desired product were collected and concentrated to give the title compound (22 mg, 9%). ESI-MS m/z [M+H]+ calc'd for C19H18N8S2, 423; found 423.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[NH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[C:24](OCC)(OCC)(OCC)[CH3:25]>CO>[ClH:1].[C:7]1([NH:6][C:4]([CH2:3][NH:2][C:24](=[N:13][CH2:14][C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:25])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)Nc1ccccc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: CO
Product: CC(=NCC(=O)Nc1ccccc1)NCC(=O)Nc1ccccc1
Yield: 20.1 %

Procedure:
0.82 Grams (4.13 millimoles) of 2-aminoacetanilide hydrochloride, 0.77 g (4.13 millimoles) of 2-aminoacetanilide (free base) were dissolved in 1.4 milliliters of hot methanol. To this solution was added 0.76 milliliters (0.67 g, 4.13 millimoles) of triethyl orthoacetate. The mixture was heated gently for five minutes. The reaction mixture was cooled and the reaction product precipitated by addition of diethyl ether. The supernatant liquid was decanted, and the precipitate was triturated with ether and collected on a filter. The product was recrystallized from ethanol, and dried to yield about 300 milligrams of N,N'-bis[phenylcarbamylmethyl]acetamidine hydrochloride.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([O-:27])(=O)=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+]>CN(C)C=O>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([Cl:3])(=[O:27])=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of thionyl chloride (0.692 ml) and N,N-dimethylformamide (0.022 ml) was added sodium 6-octyloxy-2-naphthalenesulfonate (1 g) under ice-cooling. The mixture was stirred for 1.5 hours at 95° C., then evaporated under reduced pressure to give 6-octyloxy-2-naphthylsulfonyl chloride (1 g) .
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[I:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH:24]=O>CO>[N:1]1([C:6]2[CH:7]=[C:8]([CH3:14])[C:9]3[N:13]=[C:24]([C:17]4[C:18]([O:22][CH3:23])=[N:19][CH:20]=[CH:21][C:16]=4[I:15])[NH:12][C:10]=3[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1cc(-n2ccnc2)cc(N)c1N
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(-n3ccnc3)cc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (175 mg, 0.93 mmol) in methanol (8 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (245 mg, 0.93 mmol) in methanol (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h and then at room temperature for 2 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to give the title compound (291 mg, 60%). 1H NMR (300 MHz, CD3OD) δ 8.13 (1H, s), 7.98 (1H, d, J=5.4 Hz), 7.62 (1H, d, J=5.4 Hz), 7.59 (2H, s), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). LCMS (M+H)+ m/z 432 (t=0.99 min.).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)(=[O:8])=[O:7])[CH3:2]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:7])=[O:8])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc2c(c1)CCN2)N1CC(CC)C=N1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCNC(=NS(=O)(=O)c1ccc2[nH]ccc2c1)N1CC(CC)C=N1
Temperature: 50 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
0.42 g 2,3-Dihydro-1H-indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide was dissolved in 25 mL toluene, and 10 mol % of palladium on carbon was added. The mixture was stirred at 50° C. for 5 days, with addition of fresh catalyst (10 mol %) after 2 days. The mixture was cooled to room temperature and filtered over Hyflo. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (DCM→DCM/EA 9:1) to give 0.26 g (66%) of 1H-Indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a blue oil. 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.37 Hz, 3H), 1.08 (t, J=7.22 Hz, 3H), 1.32-1.59 (m, 2H), 2.89-3.02 (m, 1H), 3.35-3.50 (m, 2H), 3.58 (dd, J=11.44, 7.52 Hz, 1H), 3.96 (t, J=11.29 Hz, 1H), 6.54-6.58 (m, 1H), 6.85 (d, J=1.50 Hz, 1H), 6.97 (br. s., 1H) 7.23-7.29 (m, 1H), 7.42 (d, J=8.73 Hz, 1H), 7.69 (dd, J=8.73, 1.81 Hz, 1H), 8.24 (d, J=1.20 Hz, 1H), 9.43 (br.s., 1H).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH2:12](Cl)[O:13][CH3:14].[H-].[Na+].CCOCC>CN(C)C=O>[Br:1][C:2]1[C:9]([O:10][CH2:12][O:13][CH3:14])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: COCCl
Reactant: O=Cc1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)c(F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluoro-5-hydroxy-benzaldehyde (750 mg, 3.41 mmol) and MOMCl (545 mg, 6.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0° C. NaH (160 mg, 60% suspension in mineral oil, 4 mmol) is then added. The resulting mixture is allowed to stir at room temperature for 1 h. Ether is then added and washed with H2O (3×20 mL) and brine. After dried over Na2SO4, the ether is removed and the residue is purified through chromatography to afford the desired MOM ether (700 mg, 78%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:14]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1NCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1CCNC1=O
Reaction time: 8 h

Procedure:
To a solution of 2-imidazolidone in toluene with an appropriate base (e.g., triethylamine) is added a solution of an equimolar amount of lauroyl chloride in toluene. This is stirred overnight, filtered and the filtrate concentrated to give the above product.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=O)=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35].[CH3:41][NH2:42]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([NH:42][CH3:41])=[O:19])=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:38])([F:40])[F:39])(=[O:35])=[O:36]
Reactant: CN
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Product: CCCCc1nc(Cl)c(C(=O)NC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1

Procedure:
A solution of the product of Example 65 (0.17 g) in methylamine (10 ml) was heated at 50° for 18 hours. The solvent was allowed to evaporate. The residue was dissolved in dichloromethane (50 ml) and washed with hydrochloric acid (2M:50 ml). The organic solution was purified by column chromatography eluting with dichloromethane/methanol (20:1) to give the title compound as a white foam (0.136 g) m.p. 89°-92° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12](O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[CH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1CC=CC(=O)O1

Procedure:
6-t-Butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (1.0 parts) was dissolved in toluene and p-toluenesulphonic acid (0.1 parts) was added. The reaction mixture was heated at reflux with removal of water via a Dean and Stark apparatus. The cooled reaction mixture was then washed with water and evaporated to give 6-t-butyl dimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.3 parts).
Reaction SMILES: C[C:2]1([C:5]([C:7]2[C:12]3[N:13]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]5[C:21]([CH3:28])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[C:14]4=[N:15][C:11]=3[C:10]([Cl:29])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1.O1[CH2:34][CH2:33][CH2:32]C1>>[Cl:29][C:10]1[C:11]2[N:15]=[C:14]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:17][CH2:18][CH2:19][N:13]3[C:12]=2[C:7]([C:5]([CH:2]2[CH2:3][CH2:4]2)([CH:32]2[CH2:33][CH2:34]2)[OH:6])=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(=O)C4(C)CC4)c23)c(C)n1
Reactant: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of methyl [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanone (145.7 mg, 0.365 mmol) in tetrahydrofuran (2.0 mL) was added c-propylmagnesium bromide (1.0 M solution in tetrahydrofuran, 3.42 mL, 3.420 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-55% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (105.5 mg, 0.240 mmol, 70%).
Reaction SMILES: C([N:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:7][CH2:6][C@@H:5]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)C=C.O>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)[NH:4]2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: C=CCN1[C@@H](c2ccc(Cl)c([N+](=O)[O-])c2)CC[C@@H]1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2)ccc1Cl
Temperature: 100 °C
Yield: 73.4 %

Procedure:
The product from Example 115A (2.0 g, 4.74 mmol) was dissolved in acetonitrile (40 mL) and water (4 mL) and treated with Tris(triphenylphosphine)rhodium(I) chloride (0.219 g, 0.237 mmol). The mixture was heated at 100° C. and nitrogen was bubbled through the solution for 3 hours. The mixture was partitioned between 5% sodium bicarbonate solution and ethyl acetate, then the organics were concentrated and the product purified by combiflash 80 g silica column eluting with dichloromethane to give 1.33 g (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:4]2[N:9]([C:10]=1[C:11](OCC)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]1(C)[CH:40]=CC=C[CH:36]=1>COC(OC)(C)C>[OH:12][C:11]1[C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[C:3]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[C:2]=2[N:1]=[C:35]([CH3:40])[CH:36]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)c2ccccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COC(C)(C)OC
Product: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-amino-3-ethoxycarbonyl-1-(2,4,6-trimethylphenyl)-indolizine (19.2 g; 59.6 mmol) in 2,2-dimethoxypropane (100 mL) is added di-camphorsulfonic acid (0.2 g). The mixture is stirred at reflux for 30 minutes and then distilled slowly to remove ca. 60 mL of volatiles over a 30-minute period. The solution is cooled to ambient temperature under an inert atmosphere, diluted with anhydrous toluene (50 mL), and concentrated in vacuo. The residue is dissolved in toluene (50 mL) and to the stirred solution is then added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (250 mL; 125 mmol) dropwise over a 1-hour period. After the addition is complete, the mixture is further stirred for 2 hours at room temperature before being concentrated in vacuo to a small volume and then diluted with aqueous ammonium chloride. The resulting emulsion-like biphasic mixture is suction-filtered and washed succesively with water, methanol, and ethyl ether. Air- and vacuum drying provides 10.1 g of the title compound as a pale yellow solid (54%).