Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[SH:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([S:28][C:29]3[S:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:33]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: CCCC(O)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(1-hydroxybutyl)benzyl]oxy}phenyl)propanoate (0.500 g, 1.34 mmol), 2-mercapto-4-phenylthiazole (0.284 g, 1.47 mmol) and triphenylphosphine (0.700 g, 2.67 mmol) in toluene (10 mL) was added diethyl azodicarboxylate (40% toluene solution, 1.21 mL, 2.67 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (0.555 g, yield 76%) as a colorless oil.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:11]=[CH:10]2.[CH3:25][CH2:26][O:27][C:28]([C:30]([C:33](OCC)=[O:34])([CH3:32])[CH3:31])=[O:29]>C1COCC1>[CH2:26]([O:27][C:28](=[O:29])[C:30]([CH3:32])([CH3:31])[C:33]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)=[O:34])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
t-Butyl lithium 1.7 M (99.7 mL, 169.5 mmol) was added slowly to a solution of (6-bromo-naphthalen-2-yloxy)-tert-butyl-dimethyl-silane (26.0 g, 77.1 mmol) in THF (400 mL) cooled to −78° C. under a nitrogen atmosphere. The reaction was stirred at −78° C. for 1 h, and then diethyl dimethyl malonate (43.5 g, 231.2 mmol) was added rapidly. The reaction was stirred an additional 0.5 h, warmed to room temperature, and partitioned between water saturated with KH2PO4 and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give 3-[6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-2-yl]-2,2-dimethyl-3-oxo-propionic acid ethyl ester as an oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22].Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H](C)CNc1c(C(=O)O)cnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Add a solution of sodium hydroxide (296.7 g, 7.42 mol, 6 eq.) in water (454 mL) to a solution of ethyl 6-bromo-4[[(2S)-2-methoxypropyl]amino]quinoline-3-carboxylate (454 g, 1.24 mol) in tetrahydrofuran (4.54 L) at room temperature. Heat the mixture at 50° C. overnight. After 18 hours, cool the reaction to 0° C., add 37% aq. HCl dropwise over 30 minutes until pH=6 (ca. 450 mL) with the temperature under 23° C. Filter the precipitate formed with filter paper and wash it with water (2 L), acetone (2 L) and methyl tert-butyl ether (2 L) subsequently. Dry the white solid to give the titled compound (359 g, 86%). MS (ESI) m/z (M+H)+ 338.9, 340.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][CH2:16][CH:17]3[O:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:5]=[CH:4][C:3]1=2.Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][C:28]1[CH:29]=[CH:30][C:25](/[C:15](=[CH:14]/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)/[CH2:16][CH:17]2[O:18][CH2:19][CH2:20][CH2:21][O:22]2)=[CH:26][CH:27]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CCC3OCCCO3)ccc21
Reactant: Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(/C(=C/c2ccc3c(c2)C(C)(C)CCC3(C)C)CC2OCCCO2)cc1

Procedure:
1.5 g (5 mmoles) of 2-[3-(5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-naphthyl)-allyl]-1,3-dioxane, 850 mg (5 mmoles) of 4-bromotoluene, 25 mg (0.1 mmole) of Pd (OAc)2, 55 mg (0.2 mmole) of P(C6H5)3 and 1.4 g (10 mmoles) of potassium carbonate are heated at 180° C. for 2 hours under passage of nitrogen.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[ClH:1].[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 3 %

Procedure:
4 M HCl in 1,4-dioxane (4 mL, 16 mmol) was added to a solution of tert-butyl 4-(5-(benzylcarbamoyl)-4-methyloxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. This was concentrated under reduced pressure, yielding 3.6 mg (3%) of the title compound as an off-white solid. LC-MS: RT=4.12 min, [M+H]+=408.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]([O:26]CC)=[O:25].[Li+].[OH-].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(C(=O)O)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 23 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
Combined ethyl 5-methoxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (401 mg, 1.032 mmol), dioxane (7 mL) and 1M aqueous LiOH (5.16 mL, 5.16 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 3 hours, and then quenched with 1N HCl(aq.) (5.16 mL, 5.16 mmol), and concentrated via rotary evaporation to furnish an off-white suspension. The suspension was filtered, rinsed with water (5×3 mL), and dried in vacuo to give the title compound (339.8 mg, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.28 (m, 2 H) 1.58-1.67 (m, 2 H) 1.75-1.88 (m, 1 H) 3.20 (t, J=6.32 Hz, 2 H) 3.27 (td, J=11.62, 2.02 Hz, 2 H) 3.82-3.90 (m, 2 H) 4.14 (s, 3 H) 7.78 (dd, J=8.59, 0.76 Hz, 1 H) 7.98 (s, 1 H) 8.40 (dd, J=8.46, 2.40 Hz, 1 H) 8.78 (t, J=5.81 Hz, 1 H) 8.98 (dd, J=2.40, 0.63 Hz, 1 H) 12.68 (s, 1 H). MS m/z [M+H]+ 361.4.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.COC(=O)C1C=CC(N2C=C(C3[C:47]([C:55]4[CH:60]=[CH:59]C=CC=4)=[N:48]OC=3C(F)(F)F)N=C2)=CC=1>>[CH:55]1([CH2:47][NH:48][C:3](=[O:31])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[CH:6][CH:5]=2)[CH2:60][CH2:59]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 69 %

Procedure:
As described for Example 10, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol), instead of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester was converted, to the title compound (75 mg, 69%) which was obtained as a white solid. MS: m/e=471.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[C@H:9]1[CH2:27][CH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:51](=[CH:52][CH:53]=1)[CH2:50][C@:40]1([C:48]3[C:43](=[N:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]1=[O:49])[CH2:39]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:28]1([CH2:27][C@H:9]2[NH:8][CH2:13][CH:12]([C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)[N:11]([CH2:22][C:23]([NH:35][C:36]3[CH:37]=[C:38]4[C:51](=[CH:52][CH:53]=3)[CH2:50][C@:40]3([C:48]5[C:43](=[N:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]3=[O:49])[CH2:39]4)=[O:24])[C:10]2=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@H]1CC1CCCCCC1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)[C@@H](CC2CCCCCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.20 g (0.42 mmol) 2-((3R)-4-(tert-butoxycarbonyl)-3-(cycloheptylmethyl)-6-(3,5-difluorophenyl)-2-oxopiperazin-1-yl)ethanoic acid (isomer 3.1.1.1), 0.11 g (0.45 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.55 mmol) 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 74 mg (0.55 mmol) HOBT, 0.06 ml (0.45 mmol) TEA and 2.0 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid for 2 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]([CH2:5][C@@H:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH2:8])[OH:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:55]([CH2:58][C@H:59]([O:63][C:64](=[O:80])[CH:65]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:60](O)=[O:61])(=[O:57])[NH2:56]>C(#N)C>[CH2:73]([CH:65]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([O:63][C@H:59]([C:60](=[O:61])[NH:1][C@@H:2]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[C@@H:3]([OH:4])[CH2:5][C@@H:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH2:8])[CH2:58][C:55](=[O:57])[NH2:56])=[O:80])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: NC(=O)C[C@H](OC(=O)C(Cc1ccccc1)Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(N)=O)OC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
100 mg of (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol in 20 ml of acetonitrile were treated with 0.080 ml of Hunig base, 174 mg of BOP and 140 mg of (S)-3-carbamoyl-2-(dibenzylacetoxy)propionic acid and stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were washed with sodium carbonate solution and, finally, dried over sodium sulfate. The solvent was then removed under reduced pressure and the residue was chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol, to obtain 142 mg (60%) of (S)-2-carbamoyl-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2 -hydroxy-4-isopropyl-5-hexenyl]- carbamoyl]ethyl dibenzylacetate in the form of a resin. MS: 591 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ncc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ncc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=420.83.
Reaction SMILES: N12CCN(CC1)CC2.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][NH:37]2>ClCCCl.[Cl-].[Na+].O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(/C=C/c1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1ncnc2[nH]cnc12
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(/C=C/c1cccc(Oc2ncnc3[nH]cnc23)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
To a mixture of 1,4-diazabicyclo[2.2.2]octane (0.098 g, 0.87 mmol) in DCE (25 mL) was added (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)-acrylamide (300 mg, 0.87 mmol) and 6-chloro-9H-purine (1.95 mmol). TEA (366 μL, 2.61 mmol) was added, and the resulting solution was stirred at 60° C. The solution was diluted with brine and extracted with EtOAc. The combined organic solutions were dried over Na2SO4, filtered and concentrated. Purification by column chromatography (SiO2, 10-80% EtOAc in hexanes) provided the title compound as a white solid (45 mg). 1H NMR (400 MHz, d6-DMSO): 813.68 (br s, 1H), 10.67 (s, 1H), 8.55 (bs, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 7.92 (dd, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.60 (m, 2H), 7.38 (d, 1H) and 6.80 (d, 1H). LCMS, AA: Rt=1.71 min, [MH+ 460.0].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=O)=[CH:18][CH:17]=2)[CH:7]=1.[NH3:28]>CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:28])=[O:25])=[CH:18][CH:17]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 63 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.047 g, 0.13 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford the title compound (0.027 g, 63%) as a white solid. MW=334.37. 1H NMR (DMSO-d6, 500 MHz) δ 8.24 (s, 1H), 8.16 (s, 1H), 7.49-7.43 (m, 2H), 7.32-7.25 (m, 3H), 7.17 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.37 (s, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H); APCI MS m/z 335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=O)=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=[C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 92.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (1 eq.) and triethylamine in ethanol at room temperature to give (92.5%) of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][Zn+]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:29][C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH3:32])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccccc1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3C)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=476 [M+Na]+.
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[CH:9]=2)[C@@H:4]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:42][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[C:10]([F:35])[CH:9]=2)[C@@H:4]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 96.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (105 mg, 0.174 mmol) prepared in Example 136a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (76 mg, 96%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[Cl-].[Na+]>C1COCC1>[CH:19]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-2-methylbenzonitrile (4.0 g, 20 mmol) in 100 mL of anhydrous THF was added BuLi (1.6 M, 12.8 mL) dropwise at −78° C. under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at −78° C. and dry DMF (2.2 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (100 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methylbenzonitrile. MS m/z: 146 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: NCCNCc1ncccn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1ncccn1

Procedure:
Treating N-(2-pyrimidylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate, then concentrating and separating by column chromatography by the procedure of Example 40 (a)(ii) gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:15]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:15])=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1cnc(Cl)cn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncc(Cl)nc1Br
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloropyrazine (1.7 g) was dissolved in chloroform (190 ml) and pyridine (1.3 ml) was added under an argon atomosphere. The flask and its contents were protected from light and a solution of bromine (0.7 ml) in chloroform (85 ml) was added over a period of 1 hour. After stirring for 2 hours more bromine (0.07 ml) in chloroform (8.5 ml) was added. After stirring for 30 minutes, pyridine (0.2 ml) was added. The reaction mixture was stirred for a further 30 minutes then washed with water (50 ml) and the organic phase was separated. Volatile material was removed by evaporation and and the residue was purified by chromatography through a bed of silica (90 g), eluting with hexane (200 ml), followed by dichloromethane. Dichloromethane fractions containing the product were evaporated to give 2-amino-3-bromo-5-chloropyrazine (1.68 g); 1H NMR (d6 -DMSO): 6.94 (br s, 2H), 8.09 (s, 1H); mass spectrum (+ve CI): 208 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]5[CH2:38][CH2:39]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(OCC2CC2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCC5CC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclopropylmethoxy-pyridine.