Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(Cl)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (250 mg, 0.88 mmol) and 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (300 mg, 1.28 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (700 μL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].OC1C2N=N[NH:41][C:40]=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.CN>C(N(CC)CC)C.ClCCl.O>[CH3:34][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:41][CH3:40])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:3])[CH3:1]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
300 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to 120 mg of hydroxybenzotriazol.H2O, 150 mg of dicyclohexylcarbodiimide, 600 mg methylamine-hydrochoride, and 30 mL dichloromethane. 0.5 ; mL triethylamine was added and the mixture was stirred for 18 h. The mixture was filtered through celite and the solvent was removed by evaporation. The resulting residue was purified by silica chromatography using hexane:ethyl acetate:dichloromethane (2:1:1) as eluent to give the title compound as a white solid; 320 mg.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.CC(C)([O-])C.[K+].[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]1[CH2:46][O:45]1.C(OCC)(=O)C>CS(C)=O>[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([OH:45])[CH2:46][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1
Reactant: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Reactant: c1ccc2cc(C3CO3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC(COCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A mixture of 6.0 g of 2-hydroxymethyl-4-tritylmorpholin, 1.0 g of potassium tert-butoxide and 6 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added, at 80°-85° C. in 2 hours, a solution of 2.8 g of 2-(2-naphthyl)oxirane dissolved in 6 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled and added to a mixture of 60 ml of ice water and 60 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 9.0 g of oily 1-(2-naphthyl)-2-[(4-tritylmorpholin-2-yl)methoxy]ethanol (compound No. 254).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]#[C:11][Si](C)(C)C)[NH:6]1)=[O:4].O[Li].O.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:19][CH2:20][C:21]([N:6]1[C@H:7]([C:10]#[CH:11])[CH2:8][CH2:9][C@H:5]1[C:3]([OH:2])=[O:4])=[O:22]
Reactant: COC(=O)[C@@H]1CC[C@@H](C#C[Si](C)(C)C)N1
Reactant: O=C(Cl)CCl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of the product from Example 19 (11.9 kg total, 308.1 g active, 1.37 mol) was concentrated to about 1240 grams and transferred to a 5-L flask. Tetrahydrofuran (1800 mL) was added and the mixture was cooled to less than 10° C. LiOH—H2O (127 g, 3.03 mol) was added over 5 minutes. After 1 hour the mixture was cooled to 0° C. and chloroacetyl chloride (339.8 g, 3.01 mol) was added over about 60 minutes. After 1.5 hours, the reaction was quenched by the addition of a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.8 kg) and isopropyl acetate (1.9 L). The layers were separated and the organic layer was washed with a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.1 kg). The combined aqueous layers were extracted with isopropyl acetate (2×2 L). The combined organic layers were concentrated several times from isopropyl acetate to dry and then to about 800 grams total weight. Solids had come out of solution during the concentration. Heptane (200 mL) was added slowly, causing more solid to precipitate. After stirring for 2-3 h, the mixture was filtered and the solids were washed with 1:1 isopropyl acetate/heptane (250 mL) and dried at 40° C. in a vacuum oven to give 255 g (86% yield) of white solid. The 1H NMR spectrum of the product exhibited 2 rotomers. Rotomer (a) was the major rotomer and rotomer (U) was the minor rotomer. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.07 (m, 2H) 2.08-2.30 (m, 2H) rotomer b: 3.13 (d, J=2.20 Hz, 1H) rotomer a: 3.46 (d, J=2.20 Hz, 1H) rotomer b: 4.09 (d, J=14.13 Hz, 1H) rotomer a: 4.32 (d, J=14.41 Hz, 1H) 4.21 (t, J=741 Hz, 7H) rotomer b; 4.40 (d, J=14.00 Hz, 1H) rotomer a: 4.59 (d, J=14.27 Hz, 1H) rotomer b; 4.61-467 (m, 1H) rotomer a: 4.77-4.85 (m, 1H) 12.53-12.85 (m, 1H)
Reaction SMILES: C([O:3][C:4]([C:6]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC=C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC=C(C)C)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10 N sodium hydroxide (10 mL) and tetrahydrofuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197° C., MS: 367.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:25])=[N:17][N:18]([CH3:24])[C:19]=1[CH2:20][CH:21]([CH3:23])[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:25])=[N:17][N:18]([CH3:24])[C:19]=2[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cc1nn(C)c(CC(C)C)c1N
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(CC(C)C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 23.6 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.35 g, 1.1 mmol) and 4-amino-1,3-dimethyl-5-isobutyl-1H-pyrazole (0.18 g, 1.1 mmol) in pyridine (4 ml) according to the method of intermediate 1, to give the title compound as an orange solid (118 mg, 0.26 mmol, 24%). δH (D-6 DMSO, 300K) 7.67 (2H, s), 6.69 (1H, s), 3.71 (3H, s), 2.45 (2H, d J 7.8 Hz), 1.90 (1H, m), 1.84 (3H, s), 0.91 (6H, d J 6.8 Hz). m/z (ES+, 70V) 456.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]2)[N:5]=[C:4]([CH:16]([O:18]C)[CH3:17])[N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH:10]([CH3:15])[NH:11][CH:12]([CH3:14])[CH2:13]2)[N:5]=[C:4]([CH:16]([OH:18])[CH3:17])[N:3]=1
Reactant: COC(C)c1nc(Cl)nc(N2CC(C)NC(C)C2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1CN(c2nc(Cl)nc(C(C)O)n2)CC(C)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cold solution of 2-chloro-4-(3,5-dimethyl-piperazin-1-yl)-6-(1-methoxy-ethyl)-[1,3,5]triazine, prepared in Example 2 above, (2.2 mmol, 631 mg) in methylene chloride (7 mL) was added boron tribromide (1 M in methylene chloride, 11.04 mmol, 11 mL) and the reaction was stirred for 2 h. After the reaction was allowed to come to room temperature, methylene chloride (10 mL) was added to it followed by a small quantity of water (1 mL) to quench the unreacted boron tribromide. Sufficient saturated aq. sodium bicarbonate was added to raise the pH of the reaction solution to 8. The methylene chloride layer was collected, dried, filtered and the filtrate was evaporated to dryness to obtain a residue, which was purified by silica gel chromatography (eluent, 98:2 methylene chloride-methanol) to obtain 1-[4-chloro-6-(3,5-dimethyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-ethanol (65%, 392 mg); mp 126-128° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:39](O)=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[C:35]([CH:36]4[CH2:38][CH2:37]4)=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:39]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[C:35]([CH:36]5[CH2:37][CH2:38]5)=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:40])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
(S)-3-amino-3-(4-chlorophenyl)propan-1-ol (173 mg, 0.93 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 64) (375 mg, 0.93 mmol) and DIPEA (0.489 mL, 2.80 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (391 mg, 1.03 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (75 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (420 mg, 79%) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.[CH2:28]1COC[CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@@H:25]([CH:26]2[CH2:29][CH2:28]2)[CH3:27])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Product: C[C@@H](Nc1nc(Cl)nc2c1COC2c1ccc(F)cc1)C1CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 14.24 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (150 mg, 0.526 mmol) in THF (2631 μL) was added (R)-1-cyclopropylethanamine, HCl (128 mg, 1.052 mmol) and DIEA (368 μL, 2.105 mmol). The mixture was heated at 40° C. for 2 h and stirred at RT overnight. The mixture was concentrated and purified by column chromatography on silica gel to give 2-chloro-N-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (Preparation Mf) (25 mg, 0.075 mmol, 14.24% yield) as a mixture of 2 diasteriomers. LC-MS (M+H)+=334.1.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C@@H:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31])=O)C1C=CC=CC=1.Br.CC(O)=O>C(Cl)Cl.O>[C:19]1([NH:18][C:17]([N:14]2[CH2:15][CH2:16][NH:11][C@H:12]([C@@H:30]([NH:32][C:33]3[N:38]=[C:37]([N:39]4[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[CH:40]4)[CH:36]=[CH:35][N:34]=3)[CH3:31])[CH2:13]2)=[O:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of (S,S)-2-[1-(1-(benzyloxycarbonyl)-4-(N-naphth-1-yl-carbamoyl)piperazin-2-yl)ethylamino]-4-[benzi midazol-1-yl]pyrimidine (24 mg) dissolved in 2 mL of CH2Cl2 and cooled to 0° C. was added 1 mL of 30% HBr/AcOH. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for an additional 2 hours while warming to room temperature. The mixture was diluted with 5 mL of water and extracted with 2×5 mL of CH2Cl2. The aqueous layer was basified to pH 11 using 5N NaOH and extracted with 5×5 mL of ethyl acetate while maintaining a pH of 11. The combined organic phases were washed with 10 nL of brine, dried with Na2SO4, and concentrated to provide 9.6 mg the title compound. Mass spectrum (ESI) 493.3 (M+1).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[CH:14]=[C:13]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[C:12]([Cl:34])=[CH:11][N:10]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41].CCCCCC>C(OCC)(=O)C>[Cl:34][C:12]1[C:13]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:14][C:9]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=2)=[N:10][CH:11]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(Cl)ncc1Cl)c1c(F)cccc1F
Reactant: COc1ccc(CN)cc1OC
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(C(c3c(F)cccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)cc1OC
Temperature: 150 °C
Yield: 30.3 %

Procedure:
To an N-methyl-2-pyrrolidone solution (20 ml) of the 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]pyridine (755 mg, 1.68 mmol) obtained in Example 294 was added 3,4-dimethoxybenzylamine (0.745 ml, 5.04 mmol) under an argon atmosphere. The resulting mixture was heated at 150° C. for 5 hours. The reaction mixture was returned to room temperature and then, diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated to give the title compound (295 mg, 0.509 mmol, 30%) as a white amorphous substance.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].Cl[C:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=[C:15]([Cl:24])[CH:14]=1.Cl>CCO>[Cl:24][C:15]1[CH:14]=[C:13]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1
Yield: 68 %

Procedure:
2-Naphthylamine and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, yielding ethyl 6-chloro-4-(2-naphthylamino)nicotinate (68%). 1H NMR [400 MHz, (CD3)2SO] δ 9.91 (br s, 1H), 8.71 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 3H), 7.59-7.48 (m, 3H), 6.91 (s, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1ccccc1N=C=O
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Reaction time: 27 h
Yield: 76.4 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.36 g, 6.15 mmol) and triethylamine (170 ml, 1.23 mmol) in THF (30 ml) was added 2-methoxyphenyl isocyanate (820 ml, 6.15 mmol), and the resulting mixture was stirred for 27 h. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected by filtration to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.74 g, 76%) as a white crystallize material. mp 157-158° C.; 1H-NMR (CDCl3) δ1.46 (s, 9 H), 2.30 (s, 3 H), 3.50 (s, 2 H), 3.76 (s, 3 H), 6.43 (s, 1H), 6.83 (br d, J=8.4 Hz, 1 H), 6.95 (br d, J=8.0 Hz, 1 H), 6.98-4.99 (m, 2 H), 7.13 (brs, 1 H), 7.23 (br s, 1 H), 7.48 (d, J=8.8 Hz, 1 H), 8.14 (d, J=8.4 Hz, 1 H); MS (ESI) m/z 371 (M++H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][N:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: CNc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-phenyl-amine. MS (ESI): 448.3 (MH+).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1

Procedure:
reacting methyl isobutyrylacetate with 4-fluoro-benzonitrile to produce methyl 2-[l-amino-1-(4-fluoro-phenyl)methylene]-4-methyl-3-oxopentanate; and
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:11]3[NH:34][CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:4]([CH3:35])[CH:3]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:35])[C:5]([S:9][C:10]2[C:11]3[N:34]([CH3:37])[CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold mixture of tert-butyl 4-(4-bromo-2,6-dimethylphenylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (1.5 mmol) in THF (5 ml) at −78° C. is added a solution of LiHMDS (2 mmol). The mixture is warmed to 0° C. over 2 hours and then cooled to −78° C. Iodomethane (6 mmol) is added and the mixture warmed to room temperature over 2 hours and then stirred at room temperature for an additional 2 hours. The mixture is washed with brine and extracted with ethyl acetate (×3). The combined organic layers are dried over MgSO4 and concentrated to dryness. The crude material is purified by chromatography on silica.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[C:19](=[O:30])[NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH:28]=O)[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[O:1]1[C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH2:12][CH:27]([C@H:24]2[CH2:23][CH2:22][C@H:21]([NH:20][C:19]([C:39]3[CH:40]=[CH:41][C:35]4[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=4[CH:38]=3)=[O:30])[CH2:26][CH2:25]2)[CH2:28]1
Reactant: O=Cc1c(O)cnc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](C4COc5cnc6ccccc6c5C4)CC3)cc2N1

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using 3-hydroxy-quinoline-4-carbaldehyde, [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:31])=O>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH2:27][CH3:28])[C:24]([Cl:31])=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(S(=O)(=O)C(CC)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(S(=O)(=O)C(CC)C(=O)Cl)cc1
Temperature: 70 °C

Procedure:
2-[(4-Dodecyloxyphenyl)sulfonyl]butanoic acid (1.1 g, 26.92 mMole) was suspended in ethyl acetate (100 mL) to which was added several drops of dimethylformamide and thionyl chloride (10.0 mL, 134.6 mMole). The mixture was heated at 70° C. for 1.5 hours, cooled, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×100 mL) and the oil so obtained used as such in the next step of the reaction sequence.