Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CO)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: BrCC1C(Cl)=NC(Cl)=CC=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:17]2[N:26]=[C:27]([Cl:31])[C:28](F)=[CH:29][C:16]=2[CH2:15]1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:17]2[N:26]=[C:27]([Cl:31])[CH:28]=[CH:29][C:16]=2[CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Agent: Clc1ccc(CBr)c(Cl)n1
Product: CC(=O)N1Cc2ccc(Cl)nc2C=Cc2ccccc21

Procedure:
Compound 13C was prepared from bb and 13B by a route analogous to that used for the preparation of 1D. HPLC Rt=2.493 min; LCMS Found: (M+H)+=285.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([O-:3])=[O:2].[Br-].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[CH2:20]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl-].[Na+]>C1C=CC=CC=1.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:20]\[C:19]2[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([O-:3])=[O:2]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COc1cc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 43.3 %

Procedure:
1.54 g of 3-nitro-4-methoxybenzaldehyde and 4.45 g of 3,4,5-trimethoxybenzyltriphenylphosphine bromide were dissolved in 40 ml of benzene, and a benzene solution containing 408 mg of sodium hydride dispersed therein was added thereto and reacted for 15 hours at room temperature (about 20°-30° C.). The reaction mixture was neutralized with acetic acid, saturated sodium chloride solution was added thereto, and the resulting liquid was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (ethyl acetate:hexane=1:2 by volume) to obtain 1.27 g of the intended compound. The yield of the product was 43%.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH2:6][N:7]=[CH:8][C:9]2([CH3:23])[CH:20]([CH3:21])[CH:18]3[CH2:19][C:13]4=[C:14]([N:17]3C)[CH2:15][CH2:16][C:10]2=[C:11]4[CH:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH2:6][N:7]=[CH:8][C:9]2([CH3:23])[CH:20]([CH3:21])[CH:18]3[CH2:19][C:13]4=[C:14]([N:17]3[C:2]#[N:1])[CH2:15][CH2:16][C:10]2=[C:11]4[CH:12]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C#N
Temperature: 25 °C
Yield: 162.5 %

Procedure:
To a stirred solution of 1.68 g of cyanogen bromide and 35 ml of chloroform was added, at room temperature with stirring under nitrogen, a solution of 3.8 g of 10-chloro-1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 100 ml of chloroform. The mixture was heated at reflux for 2 hr, under nitrogen, and cooled to room temperature. Dilute aqueous sodium bicarbonate solution was added and the layers separated. The organic layer was extracted with dilute aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with ether and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 2% triethylamine/ethyl acetate) to afford 6.41 g (78%) of 10-chloro-3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo-[3,2-h][3]benzazocine.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:21][CH:22]=[CH2:23])[C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.O=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31][CH2:30]1>ClC(Cl)C>[CH3:20][O:19][C:17]([CH:16]([NH:15][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:31][CH2:30]1)[CH2:21][CH:22]=[CH2:23])=[O:18]
Reactant: C=CCC(N)C(=O)OC
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C=CCC(NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Sodium triacetoxyborohydride (11.2 g, 52.6 mmol) was added to a solution of methyl 2-aminopent-4-enoate (3.4 g, 26.3 mmol), acetic acid (2.37 g, 39.5 mmol) and benzyl 4-oxopiperidine-1-carboxylate (9.21 g, 39.5 mmol) in dichloroethane (60 mL) at room temperature. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 0 to 8% methanol in methylene chloride gradient elution), which gave the title compound (9.42 g). MS 347.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([I:19])[CH:17]=2)[N:12]=[CH:11][C:10]=1[C:20]#[N:21].[H-].[K+]>C1COCC1>[I:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:20]#[N:21])=[C:9]2[O:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: OC1CCOCC1
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(I)cc2c1OC1CCOCC1

Procedure:
Similar procedure as described in example 28a was used, starting from 4-hydroxy tetrahydropyran, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 6-iodo-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:43]([O:47][CH:48]([O:50][NH2:51])[CH3:49])[CH:44]([CH3:46])[CH3:45]>C1COCC1.C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[NH:51][O:50][CH:48]([O:47][CH2:43][CH:44]([CH3:46])[CH3:45])[CH3:49]
Reactant: CC(C)COC(C)ON
Reactant: COC(=O)CCCCCCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)NOC(C)OCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 907 %

Procedure:
Monomethyl suberate (25.0 g, 13.3 mmol, 1.0 eq) was dissolved in THF (300 mL) and DCM (300 mL). EDC.HCl (25.46 g, 13.3 mmol, 1.0 eq) was added to the stirred solution, followed by HOBt (17.95 g, 13.3 mmol, 1.0 eq) and triethylamine (48.5 mL, 34.5 mmol, 2.6 eq). O-(1-Isobutoxy-ethyl)hydroxylamine (21.9 mL, 15.9 mmol, 1.2 eq) was added to the viscous solution and the reaction allowed to stir overnight at room temperature. The reaction mixture was concentrated under vacuum, DCM (350 mL) was added and washed with water (250 mL) and brine (200 mL). The organic layer was isolated, dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a white solid (36.6 g, 91% yield) LCMS purity 88%, m/z 302 (M++H)+. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13](Cl)(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1N1CCCC1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.1 %

Procedure:
To a solution of 121(1.5 g; 5.5 mmol) in dichloromethane (14 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.86 g; 5.5 mmol) was added followed by pyridine (0.87 g; 11.0 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (20 mL) and extracted with water. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as a light red solid (86 mg).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[C:27](I)[N:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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].O1CCCC1>[CH3:23][C:24]1[NH:25][CH:26]=[C:27]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[N:28]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)c[nH]1
Yield: 8.8 %

Procedure:
400 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 229 mg of 2-methyl-4-iodo-1H-imidazole, 8 mL of tetrahydrofuran, 9.1 mg of bis(dibenzylideneacetone)palladium and 4.6 mg of tris(2-furyl)phosphine are placed in a microwave tube. The reaction mixture is heated for 50 minutes in a microwave machine set at 130° C. and then concentrated to dryness. The residue is taken up in 3.5 mL of N,N-dimethylformamide and a further 150 mg of 2-methyl-4-iodo-1H-imidazole, 10 mg of bis(dibenzylideneacetone)palladium and 5 mg of tris(2-furyl)phosphine are added, followed by heating again for 40 minutes in a microwave machine set at 120° C. The reaction mixture is filtered, the insoluble matter is rinsed with methanol and dichloromethane and the combined filtrates are concentrated under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with dichloromethane and then with a 90/10 mixture of dichloromethane and methanol. The fractions containing the pure expected product are combined and evaporated to dryness under reduced pressure to give 28 mg of 6-(2-methyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[C:17]=3[CH:28]=2)[C:3]1=[O:29].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([N:23]([CH3:34])[S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[C:17]=3[CH:28]=2)[C:3]1=[O:29]
Reactant: COS(=O)(=O)OC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)NS(C)(=O)=O)c3c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)S(C)(=O)=O
Yield: 74.9 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-N-(methylsulfonyl)-1,2-benzisothiazole-3-carboxamide (0.300 g, 0.000670 mol) in acetone is added dimethyl sulfate (0.180 g, 0.00140 mol) followed by potassium carbonate (0.250 g, 0.00180 mol). The resultant mixture is stirred one hour at reflux and concentrated in vacuo. The residue is partitioned between methylene chloride and water. The organic layer is saved and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate:hexanes to give the title compound as a white solid (0.232 g, 74.9%, mp 120-122° C.).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[O:56][C@H:55]([CH3:57])[CH2:54][NH:53][CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:53]2[CH2:52][C@H:51]([CH3:50])[O:56][C@H:55]([CH3:57])[CH2:54]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C[C@H](C)O1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,6R)-2,6-dimethylmorpholine and isolated as white solid (13.1 mg, 67%). MS (m/e): 415.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 17.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-methyl-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (9 mg, 18%). LC-MS m/e 401.29 (M+H+)
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][N:2]([CH3:3])/[CH:4]=[CH:9]/[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Cc1ccncc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccncc1C#N
Temperature: 35 °C

Procedure:
940 ml of DMF dimethyl acetal are added to a solution of 200 g of 4-methylnicotinonitrile in 940 g of DMF, and the mixture is heated under reflux at 120-110 for 3 days. The mixture is cooled to 35° C., poured into 10 liters of ice-water and cooled at 4° C. for 16 h. The precipitate is filtered off, washed with water and dried, giving 263 g of 4-((E)-2-dimethylaminovinyl)nicotinonitrile; M˜173.22 g/mol; M+H found 174, NMR corresponds.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][CH3:20])[CH:11]=2)[CH:3]=1.[CH3:21]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:21][O:8][C:6]1[CH:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH:11]=2)[NH:19][CH3:20])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CNc1cc(Oc2cc(C)nc(O)c2)ccc1[N+](=O)[O-]
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A solution of 6-methyl-4-[3-(methylamino)-4-nitrophenoxy]pyridin-2-ol produced in Example (17a) (7.85 g, 18.7 mmol), methyl iodide (4.66 mL, 74.8 mmol) and silver carbonate (10.32 g, 37.4 mmol) in chloroform (100 mL) was stirred in a nitrogen atmosphere at room temperature for five days. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 5:1) to obtain the title compound (4.87 g, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][CH:16]=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[BH4-].[Na+]>C(O)C.O>[CH3:14][C:11]([C:9]1[CH:8]=[C:7]([CH2:15][CH2:16][OH:17])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1)([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(CC=O)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(CCO)cc(C(C)(C)C)c1

Procedure:
To a solution of the title product of Example 18 (500 mg, 2.14 mmoles) in ethanol (10 ml) is added a solution of sodium borohydride (80.8 mg, 2.14 mmoles) in water (1 ml). After disappearance of starting material as judged by TLC, excess reagent is destroyed by addition of acetic acid, and the mixture concentrated. The residue is partitioned between diethyl ether and water, the organic layer dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents affords the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.O1CCCC1.[CH:16]([S:19]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])(=[O:21])=[O:20])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Cl)nc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 2,4-dichloro-6-methoxy-1,3,5-triazine (370 mg) and tetrahydrofuran (10 mL), a mixture of 2-(isopropylsulfonyl)aniline (400 mg), N-ethyl-N-isopropylpropane-2-amine (0.72 mL) and tetrahydrofuran (5 mL) was added and stirred overnight at room temperature and further stirred at 70° C. for 7 hours. The reaction mixture was cooled on ice and diluted with water (60 mL). The precipitated solid was collected by filtration, purified by silica gel column chromatography (eluent; chloroform) and then washed with hexane to give 4-chloro-N-[2-(isopropylsulfonyl)phenyl]-6-methoxy-1,3,5-triazine-2-amine (200 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.[I:12]I.[OH-].[K+].S(=O)(O)[O-].[Na+]>CN(C)C=O>[I:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][N:7]=1
Reactant: COc1ccc2[nH]ncc2c1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A solution of 5-methoxy-1H-indazole [0.815 g, Reference Example 24(a)] in dimethyl formamide (8 ml) was treated with iodine (2.80 g) and potassium hydroxide (1.16 g). The mixture was stirred at ambient temperature for 1 hour then poured into 10% aqueous sodium bisulfite solution (200 ml) and then extracted three times with ethyl acetate. The combined organic extracts were washed with water, then with brine, then dried over magnesium sulfate and then evaporated to yield 3-iodo-5-methoxy-1H-indazole (1.48 g) as a yellow solid. LC-MS (METHOD B): RT=2.96 minutes; 275 (M+H)+. (b) 4-Fluoro-3-iodo-1H-indazole
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>[Pd]>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Reactant: Brc1cncnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 4-amino-2-methylthiazole (CAS: [103392-01-4], European Patent EP 321115) instead of 2-chloro-4-aminopyridine to yield [6-Methyl-2-(2-methyl-thiazol-4-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow cristalline solid, MS (ISP): m/e=349.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide as a light yellow cristalline solid, MS (ISP): m/e=249.1 (M+H+). Palladium catalysed arylation with 5-bromopyrimidine as described in example 20 yielded the final compound as an off-white crystalline solid, MS (ISP): m/e=327.0 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH:19]C(OCC3C=CC=CC=3)=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(Cl)Cl.C(O)(=O)C>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH2:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=S)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC1N=C(C2CCCCC2)c2ccccc2NC1=S
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
1,3-Dihydro-5-cyclohexyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-thione (787 mg, 1.93 mmole) was dissolved in 40 ml of a 1:1 mixture of methylene chloride and acetic acid. The resulting solution was cooled to 0° C. and a continuous stream of hydrogen bromide gas was passed into the stirred solution for 10 minutes. The reaction vessel was capped and the reaction mixture was allowed to warm to ambient temperature over 5 hours. All volatiles were removed under reduced pressure and the yellow residual solid was azeotropically dried with toluene. This material was partitioned between 180 ml of ethyl acetate and 7.3 ml of 10% sodium carbonate solution. The resulting suspension was stirred for 5 minutes and then filtered. The filter cake was washed with ethyl acetate, dried in vacuo over phosporus pentoxide (40° C.), and triturated with ethyl acetate-hexane (1:1) to give 492 mg of the title compound (93% yield).