Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(O)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[CH3:1][C:2]1([CH3:30])[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2(C)C)OCO4)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reaction time: 1.25 h
Yield: 71 %

Procedure:
To a reaction vessel, 2 g (0.0048 mol) compound XIV, 10 ml ethanol and 50 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction was kept at room temperature for 1-1.5 h, filtrated, the filter cake was washed with ethyl acetate, dried, and 1.2 g compound II-4 was obtained, with yield of 71%. 1H NMR (D2O): δ 1.27 (s, 6H), 1.45 (m, 2H), 1.56 (q, 2H, J=6.9 Hz), 1.69 (br s, 1H), 2.00 (d, 2H, J=13.9 Hz), 3.00 (t, 2H, J=12.6 Hz), 3.37 (t, 2H, J=7.6 Hz), 3.45 (d, 2H, J=12.3 Hz), 5.96 (s, 2H), 6.79 (s, 1H), 6.86 (s, 1H); MS (ESI): m/z 317 [M-Cl]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Temperature: 160 °C
Yield: 17.5 %

Procedure:
To a microwave vial was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (139.3 mg, 0.30 mmol), piperidine (0.04 mL, 0.35 mmol), 2-methyl-2-(1-piperidyl)propanal (68.8 mg, 0.4400 mmol) and toluene (3 mL). The vial was heated under microwave conditions at 160° C. for 3 hrs. The reaction was cooled and concentrated, then dissolved in ethyl acetate (30 mL) and washed with 2M HCl. The aqueous layer was basified to pH˜7.5 with sat. NaHCO3 and washed with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated and the crude material was purified by Isolera (1%-10% MeOH/ethyl acetate) to obtain 32 mg (18%) of the title compound. MS (pos. ion) m/z: 609 (M+1).
Reaction SMILES: C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:34]([O:37][N:38]([C@H:51]1[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:54]([CH2:64][O:65][Si](C(C)(C)C)(C)C)[C:53]([CH:73]([CH3:75])[CH3:74])=[CH:52]1)[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N+:48]([O-:50])=[O:49])(=[O:41])=[O:40])[CH:35]=[CH2:36]>>[CH2:34]([O:37][N:38]([C@H:51]1[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[C@H:54]([CH2:64][OH:65])[C:53]([CH:73]([CH3:75])[CH3:74])=[CH:52]1)[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N+:48]([O-:50])=[O:49])(=[O:41])=[O:40])[CH:35]=[CH2:36]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@@H]1C=C(C)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 87.2 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (660 mg, 87%) was prepared a similar manner as described in Intermediate 81 as a yellow oil, using (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 91, 0.928 g, 1.48 mmol) as a starting material.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[C:7]1([S:4]([CH2:3][CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)c1ccccc1
Yield: 35.7 %

Procedure:
A solution of 30.7 g (0.15 mole) of 2-chloroethylphenylsulfone and 69.5 g (0.375 mole) of potassium phthalimide in 600 ml of dimethylformamide was heated overnight at 85° C. The reaction mixture was stripped to dryness and the residue was partitioned between water and chloroform. The chloroform layer was dried and filtered and solvent was evaporated from the filtrate to give an oil which crystallized on standing. The solid was triturated with isopropyl ether and the mixture cooled under refrigeration. The solid was collected by filtration and dried and recrystallized from methanol-isopropyl ether to give white crystalline product, m.p. 186°-188° C., in 35.7% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]CC)=[CH2:9])=[CH:4][N:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1
Reactant: C=C(OCC)c1cnc(Cl)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 2-chloro-5-(1-ethoxyvinyl)pyrimidine (350 mg, 1.9 mmol) in THF (15 mL) was, added aqueous HCl (1N, 15 mL). The mixture was stirred at rt for 4 h, extracted with EtOAc. The organic phase was washed with satd aq NaHCO3 and brine. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by prep TLC (PE:EA 3:1) to give 1-(2-chloropyrimidin-5-yl)ethanone (268 mg, yield 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:3]=1[CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(CS(=O)c2cccc[n+]2[O-])c(C)c1

Procedure:
To a mixture of 7.8 g (0.03 mole) of 2-(2,4,6-trimethylbenzylthio)-pyridine-N-oxide in 50 ml of chloroform were added, with stirring at less than 10° C., a mixture of 6 g (0.03 mole) of metachloroperbenzoic acid (85%) in 100 ml of chloroform. The mixture was stirred overnight at room temperature. The mixture was then washed with saturated sodium bicarbonate solution, the chloroform layer was separated and dried over sodium sulfate. The sodium sulfate was filtered off and the chloroform solution evaporated to leave a residue, which was crystallized from ethanol. The product was filtered off, and air-dried, melting point 164–166° C., yield 7.2 g. C, H, N, calculated for C15H17NO2S: % C=65.43, % H=6.22; % N=5.09. Found: % C=66.22; % H=6.63; % N=5.13.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH:52]([OH:54])[CH3:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:52]([OH:54])[CH3:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=1[F:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 23p (530 mg, 0.67 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.4 mL, 3.5 mmol) and 10% Pd/C (212 mg, 0.2 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours under H2 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=3/1 to give a few white solid. Then the solid was further purified by prep-HPLC to give the title compound 23 as a white solid (142 mg, 43%, HPLC: 97.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 487.1 [M+H]+; and 1H NMR (600 MHz, CDCl3) δ(ppm): 7.43-7.36 (m, 1H), 7.33 (m, 2H), 6.72 (m, 1H), 6.60 (m, 1H), 4.25-4.17 (m, 1H), 4.03 (m, 4H), 3.95 (m, 1H), 3.87 (m, 1H), 3.75 (m, 3H), 1.42 (t, 3H), 1.27 (d, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:29])[CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19]3[CH:20]=[N:21][N:22]([CH2:25][C:26]([OH:27])([CH3:29])[CH3:28])[CH:23]=3)[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: CSc1nc(C)c2cc(-c3cn[nH]c3)c(=O)n(C3CCCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1nc(C)c2cc(-c3cnn(CC(C)(C)O)c3)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To the solution of 8-Cyclopentyl-4-methyl-2-methylsulfanyl-6-(1H-pyrazol-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.29 mmol) in 5 ml of DMSO were added 2,2-Dimethyl-oxirane (0.03 ml, 1.20 eq.), and potassium carbonate (40.5 mg, 1.00 eq.) under nitrogen. The reaction mixture was stirred at room temperature. After two hours, no reaction. The reaction mixture was heated to 100° C. for 30 min. Some product was formed. It was continued heating for 1 hour. Starting material was gone. The reaction mixture was partitioned in EA/brine. EA layer was dried and concentrated. It was further purified by chromatography (10% MeOH/DCM). 15 mg of product was obtained at yield of 12%.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](O)=[O:17])[N:6]=1)([CH3:4])[CH3:3].CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:31][NH:32][O:33][CH3:34].CN1CCCCC1>ClCCl>[CH3:15][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:4])([CH3:1])[CH3:3])[N:6]=[C:7]([C:16]([N:32]([O:33][CH3:34])[CH3:31])=[O:17])[N:8]=1)([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1nc(C(=O)O)nc(C(C)(C)C)c1O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCCCC1
Product: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 8.4 g (33 mmol) of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinecarboxylic acid and 0.50 mL (0.47 g, 6.5 mmol) of N,N-dimethyl formamide in 120 mL of dichloromethane was cooled in ice and treated dropwise with a solution of 4.9 mL (7.1 g, 56 mmol) of oxalyl chloride in 18 mL of dichloromethane. The mixture was stirred with ice cooling for 2 hours, then filtered, and evaporated. The residual crude acid chloride was redissolved in 85 mL of dichloromethane and added dropwise to an ice cooled mixture of 4.0 g (41 mmol) of N,O dimethylhydroxylamine hydrochloride and 15 mL (12.2 g, 123 mmol) of 1 methylpiperidine in 150 mL of dichloromethane. The mixture was stirred at room temperature for 16 hours, then washed with 0.4 N hydrochloric acid, brine, 5% aqueous sodium bicarbonate, and brine again. The organic layer was dried (anhydrous sodium sulfate) and evaporated, and the residue recrystallized from ethyl acetate/hexane to yield 6.4 g (65%) of the amide product, mp 140° C.-142° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCCCC(=O)O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)CCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 76.3 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 4-aminobutyric acid (0.54 g, 0.0052 mol) were refluxed as above for 7 hours. Crystallisation of the product from EtOH yielded 1.1 g (76%) of 102 as a white solid: mp=218–220° C.; Rf 0.78 (A): Rf 0.84 (C): Rf 0.28 (D): 1H NMR (DMSO-d6); IR (cm−1): 2800–3250 (OH), 3050 (C═CH), 2680 (C—H), 1760 (C═O), 1712 (bs, C═O), 1560 (C═C), 1430 (C═C), 1397 (C—O), 1305 (C—O), 727 (C═CH); MS m/z (rel intensity) 277 (18), 276 (100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]CC)=[O:22])[C:12]3=[CH:11][C:10]=2[C:9]=1[CH3:26])#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[C:9]=1[CH3:26])#[N:2]
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(OCc2ccc(OC(C)C)c(C#N)c2)ccc2c1cc1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (130 mg, 0.291 mmol) in dioxane (2 mL) was added a 1 M LiOH aqueous solution (1.747 mL, 1.747 mmol). The reaction mixture was stirred at room temperature for 5 h, acidified to pH 3 with 0.5 M citric acid aqueous solution, and extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, and concentrated to give the title compound as pink solid (110 mg). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (d, J=6.0 Hz, 6H), 2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.67 (dd, J=16.5, 8.5 Hz, 1H), 2.88-2.98 (m, 2H), 3.73-3.81 (m, 1H), 3.97-4.04 (m, 1H), 4.10-4.16 (m, 1H), 4.62-4.68 (m, 1H), 4.97 (s, 2H), 6.17 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.7 %

Procedure:
To a 5 L 3 necked round bottomed flask with an overhead stirrer was added 4-chloroaniline (127.57 g, 1 mole), 1200 mL of CHCl3, and 1200 mL of saturated aqueous Na2CO3 solution. An addition funnel was attached to the flask and charged with 2,2-dimethylpropanoyl chloride (129 mL, 1.05 mole). The acid chloride was added dropwise to the vigorously stirred mixture over 1 h. The resulting mixture was stirred at ambient temperature for an additional 23 h. Some of the product separated from the mixture as white crystals. These crystals were collected by filtration. The filtrate was transferred to a separatory funnel and the layers were separated. The chloroform layer was washed with water and brine. Drying (MgSO4), filtration, and removal of the solvent in vacuo gave additional product. The two portions of product were combined and recrystallized from boiling EtOAc-hexanes to give 185.6 g of N-(4-chlorophenyl)-2,2-dimethyl propanamide as a white crystalline solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[NH:33]N.Cl>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1ccc(C)c(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Product: Cc1ccc(C)c(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1
Yield: 88 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2,5-dimethyl-phenylhydrazine×HCl according to the method described for Example 1 in 88% yield. MS: M=411.1 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([CH:8]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:13]1
Reactant: O=Cc1cccs1
Reactant: CC1=NC(C)(C)CO1
Product: CC1(C)COC(C=Cc2cccs2)=N1

Procedure:
4,4-Dimethyl-2-[2-(2-thienyl)ethenyl]-2-oxazoline (P-1894) was synthesized by reacting 2-thiophenecarboxaldehyde with 2,4,4-trimethyl-2-oxazoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:18][C:19]3([CH3:36])[CH2:22][N:21](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:20]3)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:37])[CH3:6])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:18][C:19]3([CH3:36])[CH2:20][NH:21][CH2:22]3)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:37])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CNC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.5 %

Procedure:
A suspension of 2-[7-fluoro-6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester (0.280 g, 0.540 mmol) and Pd(OH)2/C (10%, 0.140 g, 0.1 mmol) in EtOH (15 mL) was stirred under H2 (50 psi) at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 2-[7-fluoro-6-(3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester (0.275 g, crude) as an oil, which was used in the next step directly. LC/MS (Table 1, Method 3) Rt=1.026 min.; MS m/z: 353 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(Br)cc1
Yield: 102.5 %

Procedure:
Thionyl chloride (2.5 ml, 34.8 mmol) is added at ambient temperature to a solution of 4-bromophenylacetic acid (Aldrich, 5 g, 23.2 mmol) in 10 ml of toluene. The reaction medium is brought to reflux for 2 hours. After returning to ambient temperature, the toluene is evaporated and 5.55 g of raw 4-bromophenylacetyl chloride is obtained (gross yield=100%).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1cccnc1
Product: CC(C)N1C(=O)NC(c2cccnc2)c2cc3c(cc21)OCO3
Yield: 36 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (238 mg) and 3-pyridinecarboxaldehyde (100 μL) by the procedure described in example 10 in 36% yield. mp: 172-174° C. 1H NMR (CDCl3): 8.58-8.56 (m, 3H), 7.63 (m, 1H), 7.29 (m, 2H), 6.70 (s, 1H), 6.34 (s, 1H), 5.94 (d, J=1.3, 1H), 5.92 (d, J=1.3, 1H), 5.33 (s, 1H), 5.29 (s, 1H), 4.41 (m, 1H), 1.53 (d, J=6.8, 3H), 1.50 (d, J=6.8, 3H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]1[CH:16]=[N:17][N:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=1)[N:11]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:10][C@H:9]([CH3:29])[N:8]2[C:30](=[O:32])[CH3:31])(=[O:3])C.[C:33](OC(=O)C)(=[O:35])C>>[C:30]([N:8]1[C:7]2[C:12](=[CH:13][C:14]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:21][CH2:22]4)[CH:19]=3)=[C:5]([NH:4][C:1]([O:35][CH3:33])=[O:3])[CH:6]=2)[N:11]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:10][C@@H:9]1[CH3:29])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Product: COC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-((methoxycarbonyl)amino)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235), substituting methyl chloroformate for acetic anhydride. MS (ESI, pos. ion) m/z 456 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Br)=[O:13]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:12](=[O:13])[CH2:11][Br:10]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Br)CBr
Product: Cc1cccc(C)c1NC(=O)CBr

Procedure:
2,6-dimethylaniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]1([C:15]2([NH2:19])[CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:19][C:15]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH2:17][CH2:18]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NC1(c2ccccc2)CCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccc(NC2(c3ccccc3)CCC2)nc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 6.7 %

Procedure:
To a 20 dram vial was added 5-bromo-2-fluoropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120° C., stirred for 72 h, and then diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give 102 mg (26%) of 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as a pale yellow solid.