Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:23]=[C:22]([CH3:33])[CH:21]=1)=[O:4].ClC1C=CC=CC=1S([C@H]1C[N:47]([C:49](=S)[CH2:50][C:51](=O)[CH3:52])[C@H]([C:55]([O:57]C)=[O:56])C1)(=O)=O.[NH:59](CCN1CCOCC1)N>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:24]([CH2:25][CH2:26][NH+:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:23]=[C:22]([CH3:33])[CH:21]=2)[C@H:5]([C:3](=[O:4])[NH:59][C:50]2([C:49]#[N:47])[CH2:52][CH2:51]2)[CH2:9]1)(=[O:12])=[O:11].[CH:55]([O-:57])=[O:56]
Reactant: NNCCN1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCN1CCOCC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CC[NH+]2CCOCC2)n1
Product: O=C[O-]

Procedure:
(2S,4R)-4-(2-Chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester. In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with 4-(2-hydrazinoethyl)morpholine (CAS Reg. No. 2154-24-7) to give the title compound as yellow oil. MS (ESI): m/z=497.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Li][C:15]#[N:16].C(P(=O)(OCC)OCC)#N.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:15]#[N:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: [Li]C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCC=C2C#N
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 339.9 %

Procedure:
5-Methoxy-1-tetralone (8.80 g) was dissolved in 50 ml of anhydrous THF and cooled to 5° C. under N2 atmosphere. LiCN (0.50 g.) was added to the stirred solution, followed by dropwise addition of diethyl cyanophosphonate (9.1 ml) over 10 min. After 45 min at 5° C., the reaction was poured into 200 ml H2O and extracted with EtOAc (3×100 ml) The combined organic extracts were washed with water (3×150 ml), saturated NaCl (150 ml), dried (MgSO4), and evaporated under reduced pressure. The resulting colorless oil was dissolved in benzene (100 ml) and p toluenesulfonic acid (0.50 g) was added. The reaction was stirred at reflux for 2 hr, cooled to room temperature, and poured into 5% NaHCO3 solution (150 ml). The reaction was extracted with Et2O (2×100 ml) and the combined organic extracts were washed with saturated NaCl solution (150 ml), dried (MgSO4), and evaporated under reduced pressure to yield 9.55 g of a white solid. The product was recrystallized from MeOH to yield 7.81 g of the product as white needles.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[S:21][C:20]=2Br)[N:16]([CH3:36])[N:15]=1.IC.[Cl-].[NH4+]>C1COCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[S:21][C:20]=2[CH3:1])[N:16]([CH3:36])[N:15]=1
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2ccc(OC(F)(F)F)cc2)sc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sc(-c2ccc(OC(F)(F)F)cc2)cc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
n-Butyllithium (2.5 N in hexanes, 0.25 mL, 0.4 mmol) was added to a solution of 3-(2-chloro-6-fluorophenyl)-5-[2-bromo-5-(4-trifluoromethoxyphenyl)thien-3-yl]-1-methyl-1H-1,2,4-triazole (190 mg, 0.3 mmol) in dry THF (2 mL) at −75° C. and stirred for 1 hour. Iodomethane (66 mg, 29 μL, 0.5 mmol) was added to this reaction mixture and stirred at −75° C. for 30 minutes. After warming to 0° C., saturated aqueous ammonium chloride (2 mL) was added, followed by water (30 mL) and the mixture was extracted with ether (3×10 mL). The combined ethereal extracts were washed with water (30 mL) and brine (10 mL), dried over magnesium sulphate and chromatographed on silica to give the product (49 mg, 29%) as a yellow solid: mp 153–155° C.; 1H NMR (CDCl3) δ 7.59 (d, 2H), 7.29–7.39 (m, 3H), 7.25 (d, 2H), 7.12 (t, 1H), 4.01 (s, 3H), 2.62 (s, 3H); EI/MS 467 m/e (M−1).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.II.[I:20](O)(=O)(=O)=O>C(O)(=O)C.C(Cl)(Cl)Cl.O>[N:12]1([C:7]2[N:8]=[CH:9][C:10]([I:20])=[CH:11][N:6]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Ic1cnc(N2CCNCC2)nc1

Procedure:
In a mixture of acetic acid (5 ml), water (1 ml) and sulfuric acid (0.15 ml) was dissolved 2 g of 1-(2-pyrimidyl)piperazine which was then reacted with 0.86 g of iodine in the presence of 0.38 g of periodic acid at 100° C. for 6 hours with stirring. Chloroform was added to the reaction mixture, followed by washing with sodium hydrogen carbonate and brine. The organic layer thus obtained was dehydrated, filtered and concentrated under vacuum. Purification with column chromatography provided the title compound. 600 mg.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[S:28]([O:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1)([CH3:27])(=[O:30])=[O:29]
Reactant: OC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.2 g of 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a mixture of 16.8 ml of pyridine and methane sulphonylchloride, after which the mixture is stirred for 2 hours at 0°C and then another 2 hours at room temperature. After that the mixture is poured out into water and then extracted with ether. The ether layers are dried and evaporated to dryness.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](O)[CH3:13]>OS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(O)c1

Procedure:
A solution of 55 g of 3-hydroxyphenylacetic acid in 400 ml of 100° ethanol is refluxed overnight in the presence of a few drops of concentrated H2SO4. It is evaporated to dryness and the residue is taken up in ethyl ether and washed with water and then with a saturated aqueous solution of NaHCO3. After drying over MgSO4 followed by evaporation, 58 g of an oil are obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]#[CH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][C:11]#[CH:12])[S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: C#CCNC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (6.55 ml) was added to an ice-cooled solution of N-methyl-N-(2-propynyl)amine (2603 mg) in methylene chloride (25 ml). Methanesulfonyl chloride (3.50 ml) was further added dropwise, the reaction mixture was stirred at that temperature for 1 hour, and then stirred further at room temperature for 2 hours. After ice was added, the reaction mixture was extracted with ethyl acetate, washed successively with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered through silica gel. The filtrate was concentrated under reduced pressure to give the title compound (4522 mg). The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:18])([C:15]([OH:17])=[O:16])[C:3]=1[C:4]=23.F[C:20]1C(C2(C([O-])=O)CO2)=C2C(=CC=1)N=CC(OC)=N2.S(=O)(=O)(O)O>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:18])([C:15]([O:17][CH3:20])=[O:16])[C:3]=1[C:4]=23
Reactant: COc1cnc2ccc(F)c(C3(C(=O)[O-])CO3)c2n1
Reactant: O=C(O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Reaction time: 17 h

Procedure:
A 3:1 mixture of 7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxaline-6-carboxylic acid and 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-oxiranecarboxylate (3.05 g) was partially dissolved in methanol (100 mL) and treated with concentrated sulphuric acid (1 mL), added dropwise at room temperature. The reaction mixture was stirred for 17 hours then quenched to pH 7 by addition of MP-carbonate resin. The mixture was filtered and evaporated. The residue was placed directly onto the top of a 100 g silica gel column and chromatographed, eluting with a 0-50% methanol in ethyl acetate gradient to afford the product (0.558 g, 17% (23% based on acid starting material).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH:21]([N-]C(C)C)(C)[CH3:22].[Li+].C(I)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]([CH2:21][CH3:22])([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (148 mg, 0.50 mmol) was dissolved in 20 mL of tetrahydrofuran. The reaction solution was cooled down to −78° C. followed by the addition of lithium diisopropylamide (0.5 mL, 1 mmol), stirred for 30 minutes, then added with ethyl iodide (156 mg, 1 mmol) and stirred for another 4 hours. The reaction mixture was added with 50 mL of saturated ammonium chloride solution, concentrated under reduced pressure and and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-chloro-8-cyclopentyl-7,7-diethyl-5-methyl-pteridin-6-one 42a (100 mg, yield: 62.0%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1.CC(=O)OCC>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: NCCc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S(=O)(O)CCCNCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-Bromophenethylamine (4 g, 20 mmol) and 1,3-propane sultone (2.56 g, 21 mmol) in acetonitrile (390 mL) was heated at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×5 mL) air-dried for 15 minutes (9.57 g), and further dried for 15 minutes in vacuo (8.02 g). The solid was suspended in ethanol (40 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature. The solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. for 18 hours. Compound EA was obtained as a white solid (6.04 g, 18.8 mmol, 94% yield). 1H NMR (500 MHz, DMSO) δ 1.95 (t, J=6.3 Hz, 3H), 2.63 (t, J=6.1 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 3.09 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.8 Hz, 2H), 7.25 (2, J=7.8 Hz, 2H), 7.53 (2, J=7.8 Hz, 2H), 8.63 (br s, 2H). 13C NMR (125 MHz, DMSO) δ 21.8, 31.0, 46.7, 47.2, 48.8, 119.9, 131.0, 131.4, 136.5. ES-MS 324 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH:12]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:18]=2)=[O:16])[CH3:13])[CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>CO>[ClH:35].[NH:8]1[CH2:9][CH:10]([CH:12]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:18]=2)=[O:16])[CH3:13])[CH2:11]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CNC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 218.7 %

Procedure:
To a solution of 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (150 mg, 0.23 mmol) in MeOH (4 mL) at 0° C. was added acetyl chloride (0.33 mL, 4.69 mmol) dropwise over 5 min. The reaction mixture was stirred at room temperature for 1 h as a thick precipitate gradually formed. The solvent was evaporated at room temperature and the residue was dried under high vacuum to isolate 145 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride as a yellow solid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[C:40]3[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=3[S:38][CH:37]=2)[C:31]([F:46])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]2[S:38][CH:37]=[C:36]([CH2:35][NH:34][C:32]3[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:11][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:10][CH2:1][O:2][C:3]=5[CH:4]=4)[N:33]=3)[C:40]=2[CH:41]=1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccc(Cl)cc12
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1NCc1csc2ccc(Cl)cc12

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.08 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=8.7 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.63 (s, 1H), 7.42 (dd, 1H, J=1.8 and 9.3 Hz), 7.07 (bs, 1H), 6.85 (dd, 1H, J=2.4 and 8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.77 (s, 1H), 4.75 (s, 1H), 4.14 (s, 4H); LCMS: ret. time: 25.89 min.; purity: 97%; MS (m/e): 444 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.OB(O)[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:16][CH2:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:16][CH2:15]3)=[N:3][CH:4]=1
Reactant: COc1ccc(I)nc1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(B(O)O)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(C#N)cc2)nc1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
394 mg 2-Iodo-5-methoxypyridine, 500 mg 4-(5-Dihydroxyboranyl-2,3-dihydro-indole-1-sulfonyl)-benzonitrile and 1.49 g cesium carbonate were dissolved in a mixture of 5 ml water and 17 ml dimethylformamide. The reaction mixture was degassed with argon and then 88 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 90° C. for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 307 mg 4-[5-(5-Methoxy-pyridin-2-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(NCC)C.C(N(CC)CC)C.[F:30][C:31]([F:35])=[C:32](F)F.CN(C)C=[O:39]>>[F:30][CH:31]([F:35])[C:32]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:39]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)F
Solvent: CCN(CC)CC
Solvent: CCNCC
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 25 °C
Reaction time: 21 h
Yield: 65 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.52 g, 2.0 mmol), diethylamine (0.44 g, 6.0 mmol), triethylamine (0.61 g, 6.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene in the flask atmosphere (0.70 g, 7.0 mmol), which was supplied from a balloon tothe flask, at 50° C. for 21 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3(3-trifluoromethylphenyl)-5-methylthiazoline (0.44 g, 1.3 mmol, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(Nc2cnccn2)ncn1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 2-aminopyrazine (230 mg, 2.42 mmol), sodium tert-butoxide (232 mg, 2.42 mmol) and bis(tri-t-butylphosphine)palladium (0) (51 mg, 0.1 mmol) in toluene (2 mL) was degassed under a stream of nitrogen over 10 min. 4,6-Dichloropyrimidine (300 mg, 2.01 mmol) was added to the mixture and the reaction was heated at 80° C. for 2 h. After cooling, the solution was passed through a PS-SH cartridge and the solvent removed in vacuo. The residue was triturated with dichloromethane and the resulting solid was collected and dried by vacuum filtration to give crude 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (333 mg) which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13](Br)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2].[OH-].[K+]>CN1CCN(C)C1=O.O>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]=[CH:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(=O)N1c2cccc3c2C(CC=C3)C1c1ccccc1
Temperature: 110 °C
Yield: 85.5 %

Procedure:
A portion (5.60 g) of the compound obtained in Example 161 was dissolved in dimethylimidazolidone (DMI; 100 ml) and to the solution was added potassium hydroxide powder (1.46 g). The mixture was heated for 1 hour at 110° C. and allowed to cool. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 3.70 g (86%) of the titled compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[N+:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[C-:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:18]=[N:17][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of ethyl isocyanoacetate and subsequently with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at room temperature for 48 hours. After distillation of the solvent, the residue is extracted with ethyl acetate/water. The crude product obtained after evaporation is chromatographed on a 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate/hexane there is obtained ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolecarboxylate in the form of yellow crystals of m.p. 109°-110°.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:23]>>[C:1]([C:9]1[C:18]([CH2:19][OH:23])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O
Product: O=C(c1ccccc1)c1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 59 %

Procedure:
A stirred slurry of 10.0 g. (0.028 mol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide in 1,000 ml. of water was heated under reflux for 18 hours. The hot reaction mixture was filtered, and the filtrate was allowed to cool to 25° C. The solid which precipitated was collected by filtration to provide a first crop of crude product. The aqueous filtrate was extracted with dichloromethane, which was then dried and evaporated in vacuo, to provide a second crop of crude product. The combined crude product was 7.0 g. (85% yield). It was recrystallized from ethanol to give 4.9 g. (59% yield) of 2-benzoyl-3-hydroxymethylquinoxaline 1,4-dioxide having m.p. 178°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:28])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([F:27])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:13]([F:28])[F:12])=[N:15][CH:16]=1)[CH2:23][C:24]1([F:27])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.93. [α]D20=25.40 (c=3.42 mg/mL,CHCl3)