Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8](I)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:17]([C:24]1[CH:25]=[CH:26][C:27]2B(O)[O:30][CH2:29][C:28]=2[CH:33]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[C:8]([C:27]3[CH:26]=[CH:25][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:33][C:28]=3[CH2:29][OH:30])[C:9]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Reactant: OB1OCc2cc(Oc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1CO)nn2C1CCCC1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
A mixture of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.36 g, 0.0011 mol), 5-phenoxy-1,3-dihydro-2,1-benzoxaborol-1-ol (0.30 g, 0.0013 mol), tetrakis (triphenylphophine)palladium (0.077 g, 0.000067 mol) and sodium carbonate monohydrate (0.34 g, 0.0028 mol) in ethylene glycol dimethyl ether (7 mL) and water (5 mL) was heated at 80° C. under an atmosphere of nitrogen for seventeen hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and aqueous saturated solution of sodium carbonate (20 mL). The aqueous layer was further extracted with ethyl acetate (3×20 mL). The organic solvent was removed under reduced pressure. Ethyl acetate (15 mL) was added to the residue and white precipitate was formed. The solid was filtered and washed with acetone (2×15 mL) and dichloromethane (1×15 mL) to yield [2-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-phenoxyphenyl]methanol (0.267 g, 0.00067 mol):
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Product: CC(C)Nc1cccc(-c2ccccc2)c1C#N
Temperature: 95 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.12 g, 0.61 mmol), and isopropylamine (3 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 95° C. for 7 days. The excess isopropylamine was evaporated, .and the residue was flash chromatographed on silica gel eluted with 0-3% ethyl acetate in hexane, and then crystallized from hexane to give the title product as a white crystalline product. ES (+) MS m/e=237 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:3]1[C:14](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:15].CO.[Li+].[BH4-].[NH4+].[Cl-]>C1COCC1>[OH:15][CH2:14][C@@H:3]1[N:2]([CH3:1])[C:6](=[O:7])[CH2:5][C@@H:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a 0° C. solution of 3-[((2R,3R)-1-methyl-5-oxo-3-phenylpyrrolidin-2-yl)carbonyl](4S)4-benzyl-1,3-oxazolidin-2-one (41.02 g, 0.108 mol) and MeOH (4.83 mL, 0.119 mol, 1.1 equiv) in THF (500 mL) was added LiBH4 (2.60 g, 0.119 mol, 1.1 equiv) in two portions. The reaction was allowed to warm to room temperature and stirred overnight, then cooled to 0° C. and treated with a saturated NH4Cl solution (100 mL). The resulting mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (3×200 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was dissolved in a minimal amount of CH2Cl2, then diluted with Et2O. The resulting precipitate was collected by filtration and washed with Et2O to give (4R,5R)-5-(hydroxymethyl)-1-methyl-4-phenylpyrrolidin-2-one (10.4 g, 47%) as a white solid: TLC (5% MeOH/CH2Cl2) Rf 0.48; 1H NMR (CDCl3) δ 2.54 (dd, J=8.4, 16.6 Hz, 1H), 2.79 (s, 1H), 2.90-3.03 (m, 4H), 3.33 (dd, J=8.4, 16.6 Hz, 1H), 3.61-3.83 (m, 3H), 7.25-7.39 (m, 5H); 13C NMR (CDCl3) δ 28.6, 35.6, 41.6, 59.6, 65.5, 127.2, 128.0, 128.7, 137.7, 146.5, 175.2; HPLC ES-MS m/z (rel abundance) 206 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:3]=[O:4].[CH2:13]=[CH:14][CH:15](O)[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH3:17])[CH:3]=[O:4]
Reactant: CC(C=O)CSc1ccccc1
Reactant: C=CC(O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC/C=C/CC(C)(C=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 1-penten-3-ol (21.67 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) are added to 90 ml of xylenes. The reaction mixture is heated to reflux using a Dean-Stark trap to collect water. After 3 hours, the mixture is cooled to room temperature and quenched with 30 ml of saturated NaHCO3 solution. The two phases are separated and the aqueous phase is extracted with 30 ml of ethyl acetate. The combined organic extracts is washed with 30 ml of brine and dried with Na2SO4. After removing solvents, the crude product is purified by chromatography. The product is obtained in 77% as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[NH2:10])=[O:4].[OH-].[Na+]>CO>[NH2:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2F)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2ccccc2F)c1C(=O)O
Yield: 56.4 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylate (6.0 g, 25.40 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (3.18 g, 14.33 mmol, 56%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[CH:17]=[CH:16][C:15]=1[N+:33]([O-:35])=[O:34].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([NH:13][C:14]3[C:15]([N+:33]([O-:35])=[O:34])=[CH:16][CH:17]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH2:21]4)[N:19]=3)=[O:12])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=C(O)C1(n2cc(Cl)cn2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C([C@@H]1CCCN(c2ccc([N+](=O)[O-])c(NC(=O)C3(n4cc(Cl)cn4)CC3)n2)C1)N1CCCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Into a 1-L Atlas jacketed reactor were added 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylic acid (49.08 g, 263.02 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (70 g, 219.19 mmol), 4-dimethylaminopyridine (5.41 g, 43.84 mmol), toluene (600 mL) and diisopropylethylamine (95.56 mL, 547.96 mmol). The reaction mixture was heated to 45° C. and stirred for 10 min until most of the solids were dissolved. 1-Propanephosphonic acid cyclic anhydride (195.70 mL, 328.78 mmol, 50% solution in ethyl acetate) was added and the temperature was increased to 110° C. The reaction mixture was stirred for 19 h before adding more 1-propanephosphonic acid cyclic anhydride solution (25 mL). The mixture was stirred at 110° C. for 5 h. The mixture was concentrated to a low volume via distillation with jacket temperature at 80° C. A mixture of ethanol:water (1:1, 1000 mL) was added to keep the temperature around 70° C. Once the addition was complete, the mixture was cooled to 15° C. over a period of 2 h and left granulating for 18 h. The solids were filtered and rinsed with a mixture of ethanol:water (1:1, 750 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 18 h to afford (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (72 g). 1H NMR (500 MHz, CDCl3) δ 1.50-1.66 (m, 4H), 1.82-2.05 (m, 11H), 2.53-2.61 (m, 1H), 3.00-3.20 (m, 2H), 3.34-3.42 (m, 1H), 3.49 (t, 2H), 6.32 (d, 1H), 7.61 (s, 1H), 7.68 (s, 1H), 8.21 (d, 1H), 11.01 (s, 1H); MS (ES+) (M+H) 488; HPLC retention time: 7.520 min (Method: Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase B: 0.1 M phosphoric acid (H3PO4) in water; Mobile Phase D: acetonitrile; Gradient: 80%-10% Mobile Phase B until 7.00 min; hold until 10.00 min; rapid ramp of 80% Mobile Phase B until 10.1 min; equilibrate until 12.1 min; Flow: 0.8 mL/min; Column Temperature: 30° C.; DAD1A, Sig=254 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C1COCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])(=[O:48])=[O:47]>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])(=[O:48])=[O:47])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CS(=O)(=O)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C

Procedure:
To a 25-mL one-neck round bottom flask with stir bar was added 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g, 0.209 mmol), pyridine (0.02 mL; 0.247 mmol) and THF (3 mL) at 0° C. To the resulting solution was added a solution of ethyl 2-(chlorosulfonyl)acetate (43 mg; 0.23 mmol) in dichloromethane (1 mL) over 10 min. The reaction was then warmed to room temperature. The reaction was quenched with 1N HCl (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM and the organics were concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield ethyl 2-((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)sulfonyl)acetate as an orange oil.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[F:13][C:14]1[CH:15]=[C:16]([NH2:27])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([N:27]=[C:1]=[S:2])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N=C=S)cc2F)CC1
Reaction time: 8 h

Procedure:
Thiocarbonyl diimidazole (3.00 g, 3.53 mmol) (Aldrich) was dissolved in N,N-dimethylformamide (10 mL) and the solution was cooled to −10° C. (ice/acetone bath). A solution of 3-fluoro-4-(4-methyl-1-piperazinyl) benzenamine (2.26 g, 10.8 mmol) (from Step B above) in N,N-dimethylformamide (30 mL) was added over a period of 30 minutes, then the cooling bath was removed and the solution was stirred overnight. Ice-water was then added (100 mL) and the mixture was extracted with ether (3×200 mL). The combined ether layers were dried (MgSO4), filtered, and evaporated to give 1-(2-fluoro-4-isothio-cyanatophenyl)-4-methylpiperazine as a yellow oil that solidified on standing (3.88 g, 92%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[CH3:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)=O)c(OC)c1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)c(OC)c1

Procedure:
The title compound was prepared as in Example 1b from 1-(4-carbomethoxy-2-methoxyphenyl)propan-2-one (3.0 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.77 g). The compound crystallised from hexane m.p. 88°-100° as a 70:30 mixture of diastereoisomers. τ(CDCl3) 8.8 (3H,d,J=6 Hz), 6.7-7.7 (5H,m,+2H replaceable by D2O), 6.1 (3H,s), 6.0 (3H,s), 5.2 (1H, m), 2.8 (2H,d,J=8 Hz), 2.2-2.6 (6H,m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(Cl)=[O:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]2[C@H:25]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27][CH:26]3[O:34][C:36]2=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1
Reactant: O=C(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)OC3Cc4ccccc4[C@@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {2′-[((1S,2R)-2-hydroxy-indan-1-ylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:28])([F:27])[C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23](Cl)(=[O:25])=[O:24])=[CH:18][CH:19]=2)[CH2:14]1)=[O:12]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:23]([C:17]2[CH:16]=[C:15]3[C:20]([CH2:21][CH2:22][N:13]([C:11](=[O:12])[C:10]([F:28])([F:9])[F:27])[CH2:14]3)=[CH:19][CH:18]=2)(=[O:24])=[O:25])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Product: Cc1ccc(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
prepared by reaction of p-tolylamine with 2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride
Reaction SMILES: [Mg].[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].BrC(Br)C.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:19]=2[N:18]=[CH:17][C:16]2=[CH:25][CH:26]=[CH:27][N:15]12.[Cl-].[NH4+]>O1CCCC1>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:19]=2[NH:18][CH:17]([CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])[C:16]2=[CH:25][CH:26]=[CH:27][N:15]12
Reactant: CN(C)CCCCl
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)CCCC1Nc2cnccc2N(C)n2cccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To magnesium turnings (1.4 g) in 10 ml of diether ether and 10 ml of tetrahydrofuran, was added a solution of 6.2 g of 3-(N,N-dimethylamino)propyl chloride in 10 ml of tetrahydrofuran. Initiation of the reaction was achieved by the addition of 1 ml of dibromoethane and the application of heat. After stirring at 70° C. for one hour, the reaction mixture was treated with a solution of 5.0 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran over a period of ten minutes. The reaction mixture was then stirred at 60° C. for thirty minutes, poured into 20 ml of an ammonium chloride solution (iced), stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with 50% methanol/dichloromethane) to afford 3.6 g (50%) of 10,11-dihydro-5-methyl-10-[3-(N,N-dimethylamino)propyl]-5H-pyrido-[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].[C:17](Cl)(Cl)=[O:18]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:16][C:17](=[O:18])[N:9]2[CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 6-chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,5-triamine (1 g, 4.1 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 40 min, a solution of phosgene in THF (3.8 mL of a 20% solution of phosgene in toluene, 7 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min, then the solvent was removed in vacuo to give 1.2 g (97% yield) of the desired product (HCl salt) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ, ppm: 11.40 (s, 1H), 7.00 (br s, 2H), 4.50-4.37 (m, 1H), 4.12-4.04 (m, 2H), 3.50 (app t, 2H), 2.68-2.55 (m, 2H), 1.78-1.71 (m, 2H); MS (EI) m/z 270.3 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:18])[CH3:17]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-(isopropyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M9;) (0.37 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (219 mg, 76%).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=1)(=O)[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=O>C1(C)C(C)=CC=CC=1>[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]1[N:8]2[N:7]=[C:6]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH:5]=[C:4]2[C:1]([CH3:2])=[N:26][N:25]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: CC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)n[nH]1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2cc3c(C)nnc(-c4ccccc4F)n3n2)cc1
Temperature: 180 °C
Yield: 94.9 %

Procedure:
A mixture of toluene-4-sulfonic acid 5-acetyl-1H-pyrazol-3-yl ester (2.52 g, 8.99 mmol) and 2-fluorobenzhydrazide (1.53 g, 9.90 mmol) in xylene (110 ml) was heated at reflux for 17 h under nitrogen. The solvent was removed in vacuo, and the residue was heated in Dowtherm A at 180° C. for 18 h The mixture was poured directly onto a column of silica gel, which was eluted with dichloromethane, then 25% EtOAc/CH2Cl2, to give 3.40 g (95%) of the title compound as a brown solid: 1H NMR (360 MHz, CDCl3) δ 2.45 (3H, s), 2.83 (3H, s), 6.71 (1H, s), 7.18 (1H, t, J=9.5 Hz), 7.30 (2H, d, J=7.8 Hz), 7.31 (1H, m), 7.59 (1H, m), 7.66 (1H, m), 7.82 (2H, d, J=8.4 Hz); MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-chloro-2-methoxyphenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methoxy-benzenesulfonamide as a colorless oil. MS: 544.8 ([M+NH4]+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH:7]([CH3:9])[CH3:8])Cl)[CH3:2].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH:7]([CH3:9])[CH3:8])[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1)[CH3:2]
Reactant: CCOC(=O)C(Cl)(c1ccccc1)C(C)C
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)(c1ncc[nH]1)C(C)C

Procedure:
12 g (0.05 mole) phenyl-isopropyl-chloroacetic acid ethyl ester (b.p. 95°C./0.3 mm Hg) are heated with 10 g imidazole and 100 ml acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted by shaking with methylene chloride. The methylene chloride is dried and distilled off in a vacuum. The phenyl-isopropyl-imidazolyl-acetic acid ethyl ester is thus obtained in the form of an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].Cl[S:34]([C:37]1[O:41][C:40]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:34]([C:37]5[O:41][C:40]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:38]=5)(=[O:35])=[O:36])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Product: COC(=O)c1ccc(S(=O)(=O)NCCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1

Procedure:
Methyl 5-({2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}sulfamoyl)furan-2-carboxylate was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and methyl 5-(chlorosulfonyl)-2-furoate following General Procedure U.