Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:11][C:10]2[C:12]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:13][C:14]([F:16])=[CH:15][C:9]=2[CH2:8][CH2:7]C1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[C:12]1[CH:13]=[C:14]([F:16])[CH:15]=[C:9]2[C:10]=1[O:11][C@@H:5]([CH2:4][NH2:1])[CH2:7][CH2:8]2
Reactant: [N-]=[N+]=NC[C@H]1CCCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-(azidomethyl)-9-(2,6-dichlorophenyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepine (0.17 g, 0.46 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.46 g, 1.4 mmol) and the reaction mixture stirred at room temperature for 2 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. The solvent was removed under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2,6-dichlorophenyl)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (0.13 g, 71%) as a white foam using excess ethereal hydrochloric acid, [α]D25=+38.22° (c 1% solution in MeOH); MS (ES) m/z 340.0 ([M+H]+).
Reaction SMILES: [CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([O:18]C(C)C)=[O:17])[C:9]([O:11]C(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O>[CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([OH:18])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
Diisopropyl (2R,3S)-2-benzyl-3-hydroxysuccinate (2.90 g; 15.9 mmol; 1.0 eq.) was taken in TIM (44 mL), cooled to 0° C. and was treated with KOH (3.17 g, 56.4 mmol) in water (14.5 mL). The resulting mixture was stirred at RT for 48 h. Tiff was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to give the title product as white solid (1.73 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=3)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 12.6 ml (90 mmol) of triethylamine, and 300 ml of dichloromethane is stirred at 0°-5° and 12 ml (94.5 mmol) of chlorotrimethylsilane is added. The reaction mixture is stirred at room for 1 hr and is cooled with a dry ice-acetone bath and 4.6 ml (35 mmol) of phenylacetyl chloride is added. The solution is stirred overnight while warming to room temperature. The dichloromethane is evaporated and water is added. The solid is filtered, washed with water and ether, and dried to give 7.0 g of 6-[4-(phenylacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280° after crystallization from 100 ml of N,N-dimethylacetamide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=C)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:31])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])=[O:14]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Yield: 100 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylene chloride (70 mL) and methanol (75 mL). Cool to -78° C. and treat with ozone until a blue color persists. Purge with nitrogen and add dimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to room temperature gradually overnight. Partition between methylene chloride (100 mL) and water (40 mL). Extract the aqueous with methylene chloride (50 mL), dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a colorless viscous oil (2.65 g, 100%).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[Cl:13][C:14]1[C:22]([CH3:23])=[C:21]([Cl:24])[C:20]([F:25])=[CH:19][C:15]=1C(Cl)=O.OS(O)(=O)=O>C1(C)C=CC=CC=1.O.C(O)C.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:22]([CH3:23])=[C:21]([Cl:24])[C:20]([F:25])=[CH:19][C:15]=1[C:4]([CH2:3][C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)c(C)c1Cl
Reaction time: 8 h

Procedure:
3 ml of ethanol and 0.5 ml of carbon tetrachloride are added to 1.4 g of magnesium turnings. After initiation of the reaction, a mixture of 8.7 g of diethyl malonate, 6 ml of ethanol and 23 ml of toluene are added at 50° C. The mixture is warmed for 1 hour at 50°-60° C. and then cooled to -5°--10° C. A solution of 13.3 g of 2,4-dichloro-5-fluoro-3-methylbenzoyl chloride (from 2,4-dichloro-5-fluoro-3-methylbenzoic acid and thionyl chloride) in 6 ml of toluene is added dropwise at this temperature. The mixture is then allowed to come to room temperature. After standing overnight, a mixture of 24 ml of water and 4 ml of H2SO4 is added. The phases are separated, and the organic phase is washed with water, dried and concentrated. 20 ml of water and 0.1 g of p-toluenesulphonic acid are added to the oily residue. The mixture is refluxed for 4.5 hours, the phases are subsequently separated, and the organic phase is dried and concentrated in vacuo. 14.1 g of the title compound remain as a crude oil. ##STR12##
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:24])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one (3 g) was suspended in 50 ml of dimethylformamide and one equivalent of 60% sodium hydride in oil was added. When gas evolution ceased, one equivalent of methyl iodide was added and the mixture allowed to stand for 1.5 hours followed by one hour at 40° C. The mixture was cooled and then poured into 200 ml of ice water, giving a precipitate that was collected by filtration, washed with water and recrystallized from ethanol. The material was further purified by chromatography on silica gel eluted with 1:1 EtOAc:Et2O yielding 0.97 g of the title product, mp 162°-165° C.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[CH3:49][O:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[C:52]=1[C:53](O)=[O:54]>>[CH3:61][O:60][C:56]1[CH:57]=[CH:58][CH:59]=[C:51]([O:50][CH3:49])[C:52]=1[C:53]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: COc1cccc(OC)c1C(=O)O
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2,6-dimethoxybenzoic acid (CAS number 1466-76-8; 151 mg, 0.83 mmol) except this was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:14]2=[O:16])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Reaction time: 2.58 h

Procedure:
0.13 ml of freshly distilled thionyl chloride are added to a mixture of 0.3 g of 1-acetyl-4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid in 3 ml of methylene chloride. The mixture is stirred for 155 minutes before being diluted with 7.5 ml of methylene chloride. The reaction solution is added dropwise to 0.17 g of aluminum chloride. Thereafter, the reaction is stirred for 15 minutes and then refluxed for three hours. The refluxed mixture is stirred for 72 hours before the sequential addition of ice, 25 ml of water and 25 ml of chloroform. The mixture is shaken and then the layers separate. The aqueous layer is extracted twice with 25 ml portions of chloroform and the combined chloroform solutions are successively washed with one 20 ml portion of a 10% sodium hydroxide solution, two 30 ml portions of water and 1 ml of saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on 20×20 cm. preparative, thick layer, silica gel plates with an acetone-ether-methylene chloride (1:1:1) mixture. The purified product is dissolved in benzene and diluted with hexane and then the solvent is removed, providing 1'-acetyl-2-fluoro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][CH:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][CH:10]3[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][C:36]1[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=1.Cl>CN1C(=O)CCC1.C(Cl)(Cl)Cl.CO.CCO.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][C:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:35][C:36]5[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=5)=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1CCl
Reactant: COc1cc(N2C=CC3C=C(c4ccc(Cl)cc4)SC3C2=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCc1cncn1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-(4-hydroxy-3-methoxy-phenyl)-3a,7a-dihydro-6H-thieno[2,3-c]pyridin-7-one (0.271 g, 0.71 mmol) in NMP (10 mL) and treat with K2CO3 (0.39 g, 2.83 mmol), and 5-chloromethyl-1-methyl-1H-imidazole hydrochloride salt (123 mg, 0.74 mmol). Stir the mixture at 80° C. overnight. Dilute the reaction with EtOAc (100 mL), wash with water (3×25 mL), dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 1% NH3—H2O, 30% CH3OH/EtOAc to give 0.105 g. Dissolve the material in CHCl3 (5 mL) and CH3OH (2 mL). Add 1.0 M HCl in EtOH (213 μL) stir. Concentrate and dry in vacuo to give 0.104 g (28%) of the title compound. LC-MS/ES m/z (37Cl) 479.0 [M+]. 1H NMR (DMSO-d6) δ 3.79 (s, 3H), 3.92 (s, 3H), 5.30 (s, 2H), 6.83 (d, J=7.2 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.5 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.88 (s, 3H), 9.07 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[N:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)#[N:22]
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: N#Cc1cccc(C=Nc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
This was prepared analogously to the above product from 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 3.61 mmol) and 3-cyanobenzaldehyde (0.47 g, 3.61 mmol) yielding 0.90 g (64%) m/z, 391.1 (M+H)+.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B-](F)(F)(F)F.CN(C(O[N:45]1[C:50](=[O:51])[CH2:49][CH2:48][C:46]1=[O:47])=[N+](C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([O:14][N:45]1[C:50](=[O:51])[CH2:49][CH2:48][C:46]1=[O:47])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
FmocSer(Bzl) (1 mmol), TSTU (1 mmol), and DIEA (2 mmol) were dissolved in DMF (6 mL). The mixture was shaken at room temperature for half an hour. The solvent was evaporated to form FmocSer(Bzl)-OSu, which was used directly in the following steps.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[CH3:17][C:18]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:19]=1[NH2:20]>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][NH:20][C:19]1[C:21]([CH3:26])=[CH:22][CH:23]=[C:24]([CH3:25])[C:18]=1[CH3:17])[CH3:2]
Reactant: Cc1ccc(C)c(N)c1C
Reactant: CCOCCOS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCOCCNc1c(C)ccc(C)c1C
Yield: 67.7 %

Procedure:
According to the method of Example 1a 553 g (2.26 moles) of p-toluenesulfonic-acid-(2-ethoxyethyl)-ester are added to a solution of 607 g (4.5 moles) 2,3,6-trimethylaniline in 1 liter of toluene. 317 g(68% of theoretical amount) of N-(2-ethoxyethyl)-2,3,6-trimethyl-aniline are obtained, b.p. 150°-152° C / 14 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1>CO.[C].[Pd]>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: COc1c(N)ccc2c1C(=CCNC(C)=O)CC2
Agent: [Pd]
Solvent: CO
Product: COc1c(N)ccc2c1C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
N-[2-(6-Amino-7-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]acetamide (2.62 g, 10.7 mmol) was dissolved in methanol (50 mL), a 10% palladium-carbon powder (500 mg) was added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.56 g, yield 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:11](I)[C:3]=12.[CH3:21][N:22](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:11]([C:21]#[N:22])[C:3]=12
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(F)cnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)c(F)cnc21
Temperature: 80 °C

Procedure:
A mixture of Example 263B (2.5 g, 5.86 mmol), zinc cyanide (0.8 g, 7.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.4 g, 0.7 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.3 mmol) in N,N-dimethylformamide (50 mL) and water (0.5 mL) was flushed with nitrogen and heated at 80° C. overnight. The reaction was quenched with brine and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 326 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[O:11]1CCOCC1>>[NH2:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH:9]=[O:11])=[CH:8][C:2]=1[CH3:1]
Reactant: C1COCCO1
Reactant: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C=O)cc(C)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.2 %

Procedure:
To a solution of 2,4,6-trimethylaniline (29.8 g, 0.22 mol) in dioxane (300 mL) DDQ (49.9 g, 0.22 mol) is added. The brown suspension is stirred at rt for 18 h before it is filtered. The solvent of the filtrate is evaporated and the crude product is purified by CC on silica gel eluting with hexane:EA 1:1 to give 4-amino-3,5-dimethyl-benzaldehyde (5.0 g) as a beige solid; LC-MS: tR=0.78 min, [M+1]+=150.26.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 116 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140 mg, 0.32 mmol), N-(4-aminophenyl)-N-methylacetamide (63 mg, 0.38 mmol) and trimethylsilyl chloride (TMSCl) (0.080 mL, 0.63 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. overnight. More N-(4-aminophenyl)-N-methylacetamide (63 mg, 0.38 mmol) was then added. The mixture was then stirred at 116° C. for an additional 24 h. It was then purified by HPLC to give N-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide as a solid (45 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCC2)c1
Temperature: 30120 °C

Procedure:
1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.6 mmol), azetidine (0.23 ml, 3.2 mmol) and potassium carbonate (0.58 g, 4.2 mmol) was dissolved in acetonitrile (10 ml). The mixture was heated in a sealed container at 30120° C. for 2 h. The reaction mixture was cooled to room temperature, CH2Cl2 (100 ml) was added, solids was filtered off and the volatiles were evaporated. The amine was converted to the fumaric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 273 (M+, 1), 94 (5), 82 (3), 71 (5), 70 (bp).
Reaction SMILES: [C:1](=[N:9][NH2:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[C:11]1([N:17]=[C:18]=[Se:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC#N>[C:11]1([NH:17][C:18]([NH:10][N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:2])=[Se:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Se]=C=Nc1ccccc1
Reactant: CC(=NN)c1ccccn1
Solvent: CC#N
Product: CC(=NNC(=[Se])Nc1ccccc1)c1ccccn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of 2.6 g (20 mmol) of 2-acetylpyridine hydrazone in 25 ml of CH3CN was added 3.6 g (20 mmol) of phenylisoselenocyanate. The clear red solution was heated with stirring to 45° C. for 3 hours, the solution was cooled to room temperature, and the crystals which separated were collected. Recrystallization of the product from EtOH gave 2.83 g (45%) of N-phenyl-2-[1-(2-pyridinyl)ethylidene]hydrazinecarboselenoamide as fine yellow needles, mp 153°-156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Br:15][C:16]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1cc(Br)c(C=CC(=O)O)cc1OC
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3Br)nc2n(CC)c1=O
Yield: 49.2 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.78 g (17.2 mmol) of 2-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.34 g (yield 49%) of Compound 117 as pale yellow needles.