Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=O.C(Br)(=O)C(Br)=O.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:33]=1[NH2:34]>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:33]=1[NH:34][C:13](=[O:15])[CH2:12][CH2:11][C:3]1[C:4]([Br:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1cc(Br)c(CCC(=O)O)c(Br)c1
Agent: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c(CCC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a −78° C. solution of 11.56 g of 3-(2,6-dibromo-4-methoxyphenyl)-propionic acid in 300 mL of CH2Cl2 was added dropwise 17.1 mL of a 1.0M solution of oxalyl bromide, then 1.7 mL of DMF. The mixture was allowed to warm to room temperature. When gas evolution ceased, the mixture was recooled to −78° C. Diisopropyl ethylamine (7.14 mL) was added dropwise, then a solution of 5.54 g of 2,6-dichloroaniline in 10 mL of CH2Cl2 was added dropwise. The mixture was allowed to warm to room temperature, then stirred overnight at this temperature. The white precipitate was collected to yield the N-(2,6-Dichlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide as a white solid. The filtrate was concentrated and recrystallized from EtOH to yield an additional amount of N-(2,6-Dichlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide as a white solid. Mass spectrum (ESI) 481.9 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 9.89 (s, 1H); 7.53 (d, J=8.2 Hz, 2H); 7.34 (t, J=8.0 Hz, 1H); 7.27 (s, 2H); 3.77 (s, 3H); 3.16 (m, 2H); 2.53 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]1[C:38]([CH2:43]Br)=[CH:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:5]3[N:4]=[C:3]([CH2:2][N:1]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36]4)[O:7][N:6]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4Cc5ccccc5C4)n3)c2[C@@H]2CCN12
Yield: 33.8 %

Procedure:
3.56 g (10 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 15 ml of methylene chloride, 8.6 ml (50 mmol) of N-ethyldiisopropylamine and 2.64 g (10 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 20 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 500 g of silica gel while eluting with methylene chloride/methanol 19/1. There were obtained 1.55 g (33%) of (S)-8-chloro-12,12a-dihydro-1-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 218°-222°.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([N:12]([CH3:14])[CH3:13])[N:5]=2)[CH2:3][CH2:2]1.[N+:15]([CH3:18])([O-:17])=[O:16].Cl.CN.C([O-])(=O)C.[Na+]>>[CH:1]1([C:4]2[N:5]=[C:6]([N:12]([CH3:14])[CH3:13])[C:7](/[CH:8]=[CH:18]/[N+:15]([O-:17])=[O:16])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CN(C)c1nc(C2CC2)ccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: CN(C)c1nc(C2CC2)ccc1/C=C/[N+](=O)[O-]
Reaction time: 4 h
Yield: 100.2 %

Procedure:
6-cyclopropyl-2-(dimethylamino)nicotinaldehyde (100 mg, 0.526 mmol) was diluted with nitromethane (199 μL, 3.68 mmol) followed by the addition of methylamine hydrochloride (21.3 mg, 0.315 mmol) and sodium acetate (25.9 mg, 0.315 mmol). After stirring for 4 hours, the reaction was loaded directly onto a silica gel column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate hexanes to yield (E)-6-cyclopropyl-N,N-dimethyl-3-(2-nitrovinyl)pyridin-2-amine (123 mg, 0.527 mmol, 100% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([NH:22][C:23]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[NH:25][N:24]=2)=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:28]1([C:26]2[NH:25][N:24]=[C:23]([NH:22][C:11]3[C:10]([CH2:9][OH:8])=[CH:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH:27]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
To a solution of 5-((tert-butyldimethylsilyloxy)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (50 mg, 0.119 mmol, 1.0 eq) in anhydrous THF (2 mL), TBAF (0.5 mL, 0.5 mmol, 4.2 equiv., 1M in THF) was added dropwise. The reaction mixture was stirred at 20° C. for 2 h and then concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 20:1 as eluent) to afford title compound (4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)methanol (Compound 123) (10 mg, 27.4%) as yellowish solid. LC-MS (m/z)=308.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.75 (m, 2H), 0.97-0.99 (m, 2H), 1.96-1.98 (m, 1H), 4.59 (s, 2H), 5.63 (s, 1H), 6.56 (s, 1H), 7.51 (m, 3H), 8.32 (m, 3H), 8.83 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:48][CH:49]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=1)[C:50]([N:52]1[CH2:55][C:54]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[CH2:53]1)=[O:51].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:64]([O:63][C:54]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[CH2:55][N:52]([C:50](=[O:51])[CH:49]([NH:48][C:16](=[O:18])[CH2:9][CH2:10][C:11]2[NH:15][CH:14]=[N:13][CH:12]=2)[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)[CH2:53]1)[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(O)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(O)cc2)NC(=O)CCc2cnc[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
0.35 ml (2.6 mmol) of triethylamine are added to a solution containing 225 mg (1.3 mmol) of desamino-histidine hydrochloride and 410 mg (1.3 mmol) of TBTU in 5 ml of DMF. After stirring for 1 hour at ambient temperature, 440 mg (0.9 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate are added. After stirring for 72 h at ambient temperature, the reaction medium is treated with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 205 mg of N-[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 47%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]=[CH:10]2)=[O:4]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(F)cc2cn[nH]c12
Product: COC(=O)c1cc(F)cc2cnn(CC(C)C)c12
Yield: 41 %

Procedure:
Compound 11 was prepared following general method 1, using 5-fluoro-1H-indazole-7-carboxylic acid methyl ester (see WO2011008572, incorporated by reference in its entirety) as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 41%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH:37]([CH3:40])[CH2:38]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:38][CH:37]([N:35]([CH3:36])[CH3:34])[CH3:40])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: CC(CCl)N(C)C
Product: COc1cc(-c2nc3ccc(OCC(C)N(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 163° C., NMR, IR, MS 543, 544.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Br:1][CH2:17][C:16]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (6.1 ml) in dichloromethane (50 ml) was added dropwise over 3 hours at 10°-15° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone (31.9 g) in a mixture of methanol (60 ml) and dichloromethane (10 ml), then the mixture was stirred at ambient temperature for 2.5 hours and poured into an excess of ice-water. The aqueous layer was separated and washed with dichloromethane 3×100 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogencarbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride, and the solvent removed in vacuo. The residue was distilled in vacuo, and the fraction of b.p. >174° C./1.3 mbar was collected and redistilled. Material of b.p. >182° C./2.6 mbar in this second distillation was collected and redistilled to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellow oil (11.8 g), b.p. 156°-162° C./0.4 mbar.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22]>CCO>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: CC(C)CC(=O)CBr
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(CC(C)C)cs2)c(Br)cn1
Temperature: 80 °C

Procedure:
In a 100 mL round-bottomed flask 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 0.95 g, 3.13 mmol) and 1-bromo-4-methylpentan-2-one (0.561 g, 3.13 mmol, Chem. Pharm. Bull., 2001, 49(8), 988-998) were mixed in EtOH (10 mL) to give a yellow suspension. The reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. ACN was added, and the residue solid was azeotroped with ACN (3×). The crude mass obtained, 1.02 g, was taken forward without purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[Na].[SH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.SC1N(C)C=CN=1.[O-]CC.[Na+]>C(O)C>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][S:22][C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cn1ccnc1S
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(Nc2ncnc3ccc(CSc4nccn4C)cc23)c1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 34, 6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with 2-mercapto-1-methylimidazole sodium salt [prepared by the reaction of 2-mercapto-1-methylimidazole and sodium ethoxide in ethanol] to give 4-(3-methylanilino)-6-(N-methylimidazol-2-ylthiomethyl)quinazoline in 65% yield, m.p. 137-139° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[N:15]1([C:20](N2C=CN=C2)=[S:21])[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([NH:14][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:21])=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2cnc(N)s2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(-c2cnc(NC(=S)n3ccnc3)s2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
To 5-(4-methoxyphenyl)thiazol-2-amine (1.07 g, 5.19 mmol) in acetonitrile (30 mL) and tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanethione (1.20 g, 6.74 mmol). The reaction was stirred at 60° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered. The powder was washed with cold acetonitrile (2×15 mL) and dried to yield N-(5-(4-methoxyphenyl)thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.59 g, 1.86 mmol, 35.9% yield) as a orange-brown powder. The product was taken directly to the next step without any further characterization.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3([CH3:15])[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:16])[O:3]1.[OH:17][CH2:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1>CCO>[OH:17][CH2:18][C@@H:19]1[N:24]([CH2:14][C:12]([OH:13])([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:16])[O:3][C@@H:2]([CH3:1])[CH2:11]3)[CH3:15])[CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: C[C@@H]1Cc2cc(C3(C)CO3)ccc2C(=O)O1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(C)(O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A solution of (3R)-3-methyl-6-(2-methyloxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (598 mg, 2.74 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (770 mg, 3.56 mmol dissolved in EtOH (15 mL) was heated in a sealed tube to 110° C. for 14 hours. The reaction was cooled and concentrated to give crude product which was purified via MPLC (30-80% EtOAc/Hexane) to give the title compound as a mixture of diastereomers: LC-MS: (M+1)+435;
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12](I)=[CH:11]2)(=O)=O)C=CC=CC=1.C(OC(=O)[N:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[C:31]([F:37])[N:30]=1)(C)(C)C>>[Cl:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[C:31]([F:37])[N:30]=1
Reactant: COc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Product: COc1ncnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c12

Procedure:
(2-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-0090 was prepared in three steps from 7-benzenesulfonyl-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine 42 and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 19 as shown in Scheme 9.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=2[O:2]1.[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:6]([C:5]1[CH:10]=[CH:11][C:12]2[O:13][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:8]
Reactant: COC(=O)c1ccc2c(c1)OCO2
Reactant: NCCN
Product: NCCNC(=O)c1ccc2c(c1)OCO2
Yield: 41.9 %

Procedure:
7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100° (bath temperature) for 2.5 hours. After cooling, the excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is made alkaline with sodium hydroxide solution and then extracted several times with chloroform. After evaporating the solvent and recrystallizing the residue from chloroform/hexane, there are obtained 3.4 g of N-(2-aminoethyl)-1,3-benzdioxol-5-carboxamide, m.p. 120°-123°. The hydrochloride melts at 210°-213°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a 2 L round bottom flask attached with condenser column and magnetic stir bar was added 1-(4-Bromo-2-chloro-phenyl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (21.1 g, 44.5 mmol), 3-methylsulfonylphenyl boronic acid (9.78 g, 48.9 mmol), PdCl2dppf (1.09 g, 3 mol %), K2CO3 (18.9 g, 137 mmol), 1,2-dimethoxyethane (250 mL) and H2O (50 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (300 mL) and aq NaCl (200 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the rotavapor and chromatographed through a 300 g SiO2 column using a mobile phase gradient of 3% EtOAc to 100% EtOAc to afford 19.3 g (79% yield) of the title compound. MS (ESI) 549.3, 551.3, 553.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]/[C:3](=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([O:15]CC)=[O:14])[S:12][C:6]=2[CH2:5]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:1][S:2]/[C:3](=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([OH:15])=[O:14])[S:12][C:6]=2[CH2:5]1
Reactant: CCOC(=O)c1nc2c(s1)CN(/C(=N/c1ccccc1)SC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS/C(=N\c1ccccc1)N1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 5-[(Z)-(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate (1 eq) obtained in step II in methanol, K2CO3 (2 eq) and few drops of water were added and the reaction mixture was stirred at room temperature for 15 h. Solvent was evaporated and the residue was treated with etheral HCl. The solvent was then evaporated and the residue was as such used for further reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nc(N)nc(-c2ccc(Br)o2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-(3-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 90).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH:16]([CH3:18])[CH3:17])[O:10]C1(C)C)=O)(C)(C)C.[CH3:21][CH:22]([C:24]1[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1)[CH3:23]>>[NH2:8][C@H:12]([C:13]1[NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:22]([CH3:21])[CH3:23])=[CH:25][C:26]=2[N:31]=1)[C@H:11]([OH:10])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: CC(C)c1ccc(N)c(N)c1
Product: CC(C)c1ccc2[nH]c([C@@H](N)[C@H](O)C(C)C)nc2c1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 60) and 4-(1-methylethyl)-1,2-benzenediamine.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[C:8]([O:20][CH3:21])=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)([CH3:6])=[O:5])#[N:2].[OH:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C-]#N.[K+]>ClCCl.C(#N)C>[OH:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([C:16]([F:17])([F:18])[F:19])=[C:7]([S:4]([CH3:6])(=[N:3][C:1]#[N:2])=[O:5])[C:8]=1[O:20][CH3:21]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Reactant: Cc1cc(O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [C-]#N
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(=O)c2c(C)nn(C)c2O)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
165 mg (75% by weight; 0.384 mmol) of 3-(N-cyano-S-methylsulfonimidoyl)-2-methoxy-4-(trifluormethyl)benzoic acid and 68.9 mg (0.614 mmol) of 5-hydroxy-1,3-dimethylpyrazole were initially charged in 20 ml of dichlormethane, and 128 mg (0.666 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The mixture was stirred at RT for 16 h and, for work-up, washed with 1 M hydrochloric acid. After phase separation, the organic phase was dried, filtered and freed from the solvent on a rotary evaporator. The residue was purified chromatographically and the intermediate obtained was then dissolved in 15 ml of acetonitrile. 104 mg (1.02 mmol) of triethylamine, eight drops of trimethylcyanide and a spatula tip of potassium cyanide were then added. The mixture was stirred at RT for 16 h and, for work-up, freed from the solvent. The residue was taken up in dichloromethane and washed with 3 ml of 1M hydrochloric acid. After phase separation, the organic phase was freed from the solvent and the residue was purified chromatographically, which gave 31.3 mg of 5-hydroxy-1,3-dimethyl-4-[3-(N-cyano-S-methylsulfonimidoyl)-2-methoxy-4-(trifluoromethyl)benzoyl]pyrazole in a purity of 85% by weight.