Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)(=O)=[O:13].CCO>C(Cl)Cl>[CH3:11][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A solution of 3-nitro thioanisol (96 g, 568 mmol) in DCM (100 mL) was added dropwise to a cooled solution of sulfuryl chloride (96 g, 711 mmol) in DCM (600 mL) at −60° C. The mixture was stirred for 4 h at −20° C., then cooled to −60° C., and 350 mL of EtOH were carefully added. The reaction was then allowed to warm up to rt, subsequently, most of the solvent was evaporated, the residue was poured in sat. aq. NaHCO3, and the solid product was filtered off and carefully washed with hexane on the filter, then air-dried to give the desired sulfoxide (95 g, 90% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:17])[CH2:15][NH2:16]>>[CH3:17][C:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:13])[CH2:15][NH:16][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(C)(CN)N1CCCCC1
Product: CC(C)(CNC(=O)CN1CCCC1=O)N1CCCCC1

Procedure:
From 8.56 g. of ethyl 2-oxo-1-pyrrolidineacetate and 12.5 g. of 2-methyl-2-(1-piperidinyl)propylamine [J.A.C.S. 68, 13 (1946)], following the procedure of Example 9, there is obtained N-[2-methyl-2-(1-piperidinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 69° C. after crystallization from heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]2[NH:17][C:18]([S:20][C:21]3[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:26]([C:24]3[O:25][C:21]([S:20][C:18]4[NH:19][C:15]5[CH:14]=[C:13]([Cl:12])[C:29]([Cl:30])=[CH:28][C:16]=5[N:17]=4)=[CH:22][CH:23]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3cc(Cl)c(Cl)cc3[nH]2)o1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(Cl)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A suspension of 231.3 mg (1.5 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 469.7 mg (1.5 mmol) of 5-(5,6-dichloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1) in 7.5 mL of n-butanol under argon is stirred at room temperature until complete dissolution. 1,3-Cyclohexanedione (168.2 mg, 1.5 mmol) is then added and the reaction mixture is heated at reflux temperature for 1.5 h. The mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol 100/0 to 90/10 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is recrystallized from ethanol and the solid is filtered, washed with ethanol and dried under reduced pressure. 431 mg of 9-[5-(5,6-dichloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a beige crystalline powder. mp: 180° C. LCMS: m/z 543: [M+H]+ (base peak). EA.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:41]>O>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:44][CH:43]=1)=[O:41]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added tert-butyl 4-(4-chloropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 1.082 mmol), DMSO (5.4 mL), cesium carbonate (370 mg, 1.136 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (258 mg, 1.082 mmol) before sealing and heating to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude material was taken after purifying by column chromatography (10% methanol/dichloromethane), affording tert-butyl 4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z: 498.3 (M+1).
Reaction SMILES: O=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][NH3+:15].[Cl-].N1C=CC=CC=1>C(O)C>[CH3:13][O:14][N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(=O)OCC
Yield: 93221.8 %

Procedure:
A solution of diethyl ketomalonate 1 (51.0 g, 0.293 mmol), o-methylhydroxylamine hydrochloride (24.46 g, 0.293 mmol) and pyridine (23.2 g, 0.293 mmol) in ethanol (250 ml) is heated to reflux for 3 hr. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dilute hydrogen chloride, aqueous sodium hydrogencarbonate solution, and water successively. After drying over sodium sulfate, the solvent is removed under reduced pressure. The resultant residue is distilled under reduced pressure at 80°-85° C./0.5 mmHg to obtain Compound 2 (55.5 g, 93.2%). NNMR (CDCl3)δ: 1.35 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 4.11 (3H, s), 4.36 (2H, q, J=7.1 Hz), 4.37 (2H, q, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:11]([CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:38]1([N:41]2[CH2:13][CH2:12][N:11]([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:25][CH2:26]2)[CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)Sc2ccccc2[N+](=O)[O-])cc1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccccc1SN1CCN(C2CC2)CC1

Procedure:
A mixture of 112 g (0.198 mol) of N-(2-nitrophenylsulphenyl)-bis[2-(4-toluenesulphonyloxy)-ethyl]amine, 16.7 g (0.29 mol) of cyclopropylamine and 82 g (0.6 mol) of powdered potassium carbonate in 3.3 l of isopropanol is heated under reflux for 6 hours. Thereafter, the mixture is concentrated in vacuo, the residue is taken up in 550 ml of methylene chloride and the mixture is washed with water, dried with sodium sulphate and concentrated. For purification, the crude product is filtered over 600 g of silica gel with methylene chloride as the mobile phase and the eluate is concentrated. Yield: 47 g of melting point 100°-102°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH2:24]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=2)[C:19]([C:20]#[N:21])=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1)[CH3:25]
Reactant: C1COCCN1
Reactant: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CC#N
Product: CCn1c(-c2ccc(OCCN3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 85 °C
Yield: 96.2 %

Procedure:
2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, was combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This was heated at 85° C. for 2 h. The reaction mixture was then partitioned between CH2Cl2 and H2O. The organic layer was dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yielded 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[N:27]=[CH:26][NH:25][N:24]=1>>[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[N:24]=1
Reactant: Clc1nc[nH]n1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(Cl)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example A.17) (1.628 g, 5.0 mmol) and commercially available 3-chloro-1H-(1,2,4)triazole (0.776 g, 7 mmol) according to the general procedure IVa. Obtained as a white solid (1.651 g, 84%). MS (ISP) 393.1 [(M+H)+] and 395 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:11]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH3:10])=[C:2]([N:1]=[C:33]2[N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36](=[O:37])[C:35](=[C:38]3[N:42]([CH3:43])[C:41]4[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:40]=4[S:39]3)[S:34]2)[CH:3]=1)(=[O:13])[CH3:12]
Reactant: COCCOc1ccc2c(c1)N(C)C(=C1S[CH2+](SC)N(Cc3ccccc3)C1=O)S2
Reactant: CCNc1ccc(C(C)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccc(OCCOC)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was synthesized in a manner similar to that described in Example 146 by condensing 3′-amino-4′-(ethylamino)acetophenone with 3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate. MS(ESI): 546 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:23]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of (S)-1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (50 mg, 0.198 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.104 mL, 0.594 mmol) in acetonitrile (6 mL), was heated in a microwave reactor at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated, re-dissolved in DMF, and purified by preparative HPLC (basic mode) using a 20-30% CH3CN gradient in H2O. The desired fractions were combined and solvent was removed in vacuo. The residue was purified again by preparative HPLC (basic mode) using a 25-35% CH3CN gradient in H2O. The pure fractions were combined and the solvent was removed in vacuo to give the title compound as a colorless film (24 mg, 31%). 1H NMR (500 MHz, CD3OD) δ ppm 1.59 (d, J=7.32 Hz, 3 H), 4.04 (br s, 3 H), 5.84 (q, J=7.32 Hz, 1 H), 6.88 (d, J=3.42 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.08 (d, J=2.93 Hz, 1 H), 8.16 (td, J=7.81, 1.95 Hz, 1H), 8.66 (s, 1H), 8.83 (d, J=4.88 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19N9, 386. found 386.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(#N)C>[ClH:21].[F:20][C:2]([F:1])([F:19])[C@@H:3]([O:18][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: CN1CCN(C[C@H](O)C(F)(F)F)CC1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: CN1CCN(C[C@H](OC(=O)Nc2ccc(Cl)cc2)C(F)(F)F)CC1c1ccccc1
Product: Cl
Reaction time: 8 h

Procedure:
(S)-1,1,1-Trifluoro-3-(4-methyl-3-phenyl-piperazin-1-yl)-propan-2-ol (180 mg, 0.62 mmol) and 1-chloro-4-isocyanatobenzene (115 mg, 0.75 mmol) were combined in acetonitrile (5 mL). The reaction mixture was stirred overnight and evaporated. The residue was purified by flash chromatography (20/1 dichloromethane/EtOAc then 20/1 dichloromethane/MeOH) to provide the desired product. To the free-base product was added 1M HCl/ether solution to provide HCl salt form, (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-(4-methyl-3-phenyl-piperazin-1-ylmethyl)-ethyl ester hydrochloride (150 mg) as a white solid. (M+H)+=442 m/e.
Reaction SMILES: [CH3:1]O.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=1.Cl>O1CCOCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:1])=[O:9])=[C:6]([Cl:13])[CH:5]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Br)cc1Cl

Procedure:
To a methanol solution (25 ml) of 4-bromo-2-chlorobenzoic acid (5.0 g) was added hydrochloric acid/a 1,4-dioxane solution (4 N, 25 ml), followed by heating at reflux for 90 minutes. The reaction solution was brought back to room temperature, and concentrated under reduced pressure. Dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 4-bromo-2-chlorobenzoate (5.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: NCC(O)CO
Product: Cl
Product: O=C(Nc1nnn[nH]1)c1cc(NCC(O)CO)c2ccccc2n1

Procedure:
4(2,3-Dihydroxypropylamino)-N(1H-tetrazol-5-yl)quinaldamide, hydrochloride, m.p. 264° (d) was prepared from 4-chloro-N(1H-tetrazol-5-yl)quinaldamide (Example 2 ) and 3-amino-1,2-propanediol.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([O:7][C:8](Cl)=[O:9])=[CH:3][CH:2]=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][N:18]([C:8]([O:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[O:9])[CH2:19][CH2:20][CH:21]=1
Reactant: CON=CC1=CCCNC1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=CC1=CCCN(C(=O)Oc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
A solution of p-tolylchloroformate (1.5 mL, 10.3 mmoles) in dichloromethane (15 mL) was added under nitrogen at 0° C. to a stirred solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (1.3 g, 9.3 mmoles) and triethylamine (1.3 mL, 2.3 mmoles) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 20 minutes, the solvent was evaporated and the residue was partitioned between water and ethylacetate. The organic layer was dried (Na2SO4) and evaporated. The solid was triturated with cyclohexane to afford 2.3 g (91%) of a white solid with mp 70°-71° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)[C:12]2[N:16]([CH2:17][CH2:18][O:19][Si](C)(C)C)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)[C:12]2[N:16]([CH2:17][CH2:18][OH:19])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3n2CCO[Si](C)(C)C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3n2CCO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 10 Step A (0.13 mmol, 73 mg) in 2 mL of dioxane was added a solution of LiOH (1.25 mmol, 30 mg) in 1 mL of H2O. The resulting solution was stirred at 40° C. overnight. The reaction mixture was taken up in a pH 7 buffer solution and EtOAc. The mixture was acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford the acid as a beige solid. MS (ESI): m/z 450 (M+H). HPLC A: 2.05 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:20]3[C:21](=[O:25])[CH2:22][CH2:23][CH2:24][C:19]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C1CCCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)CCC1)C2c1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
The product from Example 45A (0.086 g, 0.75 mmol), 3-bromo-4-fluorobenzaldehyde (0.15 g, 0.075 mmol), and 1,3-cyclohexanedione (0.084 g, 0.75 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The resulting mixture was allowed to cool to ambient temperature and filtered to provide the title compound as the filter cake (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.27 (m, 2H), 2.63 (m, 2H), 3.24 (s, 3H), 4.69 (s, 1H), 7.2 (m, 1H), 7.23 (t, 1H), 7.45 (dd, 1H), 10.2 (s, 1H); MS (ESI) ml/z 393 (M−H)−; Anal. Calcd for C17H14N2BrFO3: C, 62.48;H, 3.86;N, 12.86. Found: C, 62.55;H, 4.07; N, 12.61.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:47][C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:39])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:37][CH:38]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](C)c4ccccc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 84 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 411D) and R-(+)-α-methylbenzylamine: yield 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][OH:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH:26]=[O:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CO)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.085 g, 0.19 mmol) in DMF (6 mL) was added pyridinium dichromate (PDC) (0.25 g, 0.65 mmol) at ambient temperature. After stirring for 20 hours, water was added and the reaction mixture was extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica to afford 0.035 g of N-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow solid; NMR (DMSO-d6) 11.3 (s, 1), 10.8 (s, 1), 9.9 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2) ppm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1.C([O-])(=O)C.[K+].O>C(O)C.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[F:18][C:19]1[C:24]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: C=Cc1cnc(F)c(B(O)O)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(F)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (984 mg, 3.89 mmol), 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 5.28 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (138 mg, 0.195 mmol), and potassium acetate (1.212 g, 12.35 mmol) were suspended in ethanol (12.0 mL) and water (2.4 mL) and the flask was fitted with a reflux condenser and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was put in a preheated oil bath (80° C.) and stirred under nitrogen for 1 h. The reaction was cooled to room temperature, diluted with water (20 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/2 N ammonia in MeOH) to afford 6-(2-fluoro-5-vinylpyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine, which was taken on to the next step. MS (ESI pos. ion) m/z 340 (M+H)+.