Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:7]([O:22][CH3:23])[CH:6]=2.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:41][CH2:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:7]([O:22][CH3:23])[CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.76 g, 3.66 mmol), NBS (0.846 g, 4.75 mmol) and diphenylperoxyanhydride (0.089 g, 0.366 mmol) in carbon tetrachloride (60 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:52][CH2:51][CH2:50]4)=[CH:47][C:43]([C:44]([OH:46])=O)=[C:42]([F:53])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.CS(N)(=O)=O.[N:59]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61][CH2:60]1>>[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:50][CH2:51][CH2:52]4)=[CH:47][C:43]([C:44]([NH:66][S:63]([N:59]4[CH2:62][CH2:61][CH2:60]4)(=[O:65])=[O:64])=[O:46])=[C:42]([F:53])[CH:41]=3)[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2
Reactant: O=C(O)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.043 g, 13%): 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.5 Hz, 1H), 7.88 (d, J=9.3 Hz, 1H), 6.54 (d, J=14.6 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.69-3.58 (m, 1H), 3.49 (s, 2H), 2.39-1.99 (m, 10H), 1.87-1.64 (m, 13H); MS (ES−) m/z 475.2 (M−1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=[O:15])=[O:7])([CH3:4])[CH3:3].[BH4-].[Na+]>CO>[C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:11][CH2:10][CH:9]1[CH2:16][CH:14]([OH:15])[CH2:13]2)=[O:7])([CH3:4])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. cold solution of 2.00 g N-Boc-nortropinone in 50 mL of methanol was added portionwise 672 mg of sodium borohydride. The reaction mixture was stirred at 0° C. for 1 h. The solvent was evaporated, the crude product was taken up in dichloromethane and treated with sat. sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated to give 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70) as diastereomeric mixture. Rt=1.11 min, 1.17 min (Method C). Detected mass: 128.0 (M-Boc+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:21]I>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]1[N:13]([CH3:21])[CH:12]=[CH:11][S:10]1
Reactant: CI
Reactant: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N=c2sccn2C)c(Cl)c1
Temperature: 100 °C
Yield: 62 %

Procedure:
A mixture of ethyl 2-[3-chloro-4-(N-thiazol-2-ylamino)phenyl]propionate (3.8 g), methyl iodide (11.4 ml) and ethanol (11.4 ml) is heated at 100° C for 6 hours in a sealed tube. The ethanol and methyl iodide are evaporated. The residue is washed with benzene and dissolved in methylene chloride. The solution is washed with 20 % aqueous potassium carbonate solution and evaporated to remove methylene chloride. The residue is treated in the same manner as in Example 1 to give ethyl 2-[3-chloro-4-(3-methyl-4-thiazolin-2-ylideneamino)phenyl]propionate (2.45 g). (Yield 62 %).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[CH:20][CH:21]=1>C(#N)C>[C:19]1([NH:22][C:23]2[N:25]=[C:5]([C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])[CH:4]=[CH:3][N:24]=2)[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=CC(=O)c1cccc(C#N)c1
Reactant: N=C(N)Nc1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(-c2ccnc(Nc3ccccc3)n2)c1

Procedure:
To a solution of 3-(3-dimethylamino-acryloyl)-benzonitrile (30.4 g, 152 mmol) in acetonitrile (250 mL) was added a solution of phenylguanidine (21.0 g, 155 mmol) in acetonitrile (250 mL) and the mixture was heated at reflux for two hours. The solution was cooled and the resulting solid was filtered and washed with acetonitrile to afford the title compound.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([N:15]=[C:16]=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].[N-]=C=O>>[C:1]([N:5]=[N:6][C:7]([NH:15][C:16]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])=[S:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CC(C)(C)N=NC(C)(N=C=S)c1ccccc1
Agent: [N-]=C=O
Product: CC(C)CNC(=S)NC(C)(N=NC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 9.25 grams (0.0375 moles) of 1-t-butylazo-1-isothiocyanato-1-phenylethane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.75 grams (0.0375 moles) of isobutylamine. The reaction mixture was stirred for 30 minutes at room temperature at which time an infrared spectrum of the reaction mixture showed the complete absence of the isocyanate band at 2225 cm-1. The orange liquid weighed 10.2 grams (85% crude yield) and its infrared spectrum contained a strong band around 1530 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.O>[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 0° C. mixture of 2-chloro-4-hydroxypyridine (817 mg, 6.30 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 277 mg, 6.93 mmol), stirred for 1 h, treated with 5-bromo-2,4-difluoronitrobenzene (1.50 g, 6.30 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 53%). MS (ESI) m/z: (M+H+): 348.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[CH2:15][CH:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1.C(O[K])(C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][CH:14]2[CH2:15][C:10]([CH3:19])([CH3:9])[NH:11][C:12]([CH3:18])([CH3:17])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC1(C)CC(Oc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 0 °C
Yield: 71.6 %

Procedure:
To a 30-L reactor was charged 3,6-dichloropyridazine (1 kg, 6.7 mol), 2,2,6,6-tetramethylpiperidin-4-ol (1.05 kg, 6.7 mol) and THF (5 L). The mixture was stirred and cooled to −5° C. tBuOK (1.13 kg, 10.1 mol) dissolved in THF (10 L) was added slowly to the reactor while keeping the temperature at −5-0° C. The reaction mixture became deep brown during addition. After the addition was complete, the mixture was stirred for 1 hour at −5-0° C., after which time HPLC analysis showed that the reaction was complete. Ice water (1:1, 10 kg) was added slowly to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the THF. The residue was extracted with EtOAc twice (10 L+5 L). The combined organic layer was washed with water (10 L×3), then concentrated under reduced pressure to give a black residue. Petroleum ether (25 L) was added to this residue while stirring. The dark solid that formed was removed by filtration. The pale yellow filtrate was concentrated under reduced pressure to give a yellow solid, which was dried at 50° C. in vacuo to give 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.3 kg, 4.8 mol), and was used in the next step without further purification. MS m/z 270.1 [M+H]; 1H-NMR: (CDCl3, 400 MHz) δ 7.36 (d, J=9.2 Hz, 1H), 6.90 (d, J=9.2 Hz, 1H), 5.74 (m, 1H), 2.20 (dd, Ja=4 Hz, Jb=12.4 Hz, 2H), 1.30 (m, 14H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([O:53][CH2:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:53][CH2:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-[4"-azido-3"-ethoxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (28 mg, Example 48) and triphenylphosphine (9 mg) in 1 ml of wet benzene is refluxed overnight. The solvent is removed in vacuo and the residue is purified on silica gel column to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl[CH2:11][CH:12]=O>C(O)C>[N:1]1[CH:11]=[CH:12][N:3]2[CH:4]=[C:5]([C:8]#[N:9])[N:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: N#Cc1cnc(N)cn1
Solvent: CCO
Product: N#Cc1cn2ccnc2cn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 5-aminopyrazine-2-carbonitrile (5-1) (350 mg, 2.92 mmol) in ethanol (15 mL) was added 2-chloroacetaldehyde (4 mL, 40% in water). The mixture was stirred at 110° C. overnight. The solution was concentrated, then purified by chromatography on silica gel to afford the title compound (280 mg). MS (m/z): 145.1 (M+H)+.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[NH:4][CH:3]=[N:2]1.[BH4-].[Na+].Cl>O>[S:1]1(=[O:11])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[NH:4][CH2:3][NH:2]1
Reactant: O=S1(=O)N=CNc2ncccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)NCNc2ncccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of 4H-pyrido[2,3-e][1,2,4]thiadiazine 1,1- dioxide is suspended in 30 cm3 of water. A solution of 0.83 g of NaBH4 in 5 cm3 of water is added to the suspension. After stirring for 15 minutes at ambient temperature, the pH of the solution is adjusted to 6.5-7 using dilute HCl. The precipitate obtained is filtered, washed with water and dried. The dried compound is dissolved in 200 cm3 of dichloromethane. The possible insoluble material is removed by filtration. The filtrate is treated with an equal volume of petroleum ether (40°-60° C.) and placed at +4° C. overnight. The crystals obtained are collected on a filter and dried.
Reaction SMILES: [F:1][CH:2]([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11]Cl>FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[Cl-].[K+]>[Cl:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:10])[F:1]
Reactant: ClCl
Reactant: FC(F)Oc1ccccc1
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [K+]
Product: FC(F)Oc1ccccc1Cl

Procedure:
0.5 g of potassium chloride and 10 g of difluoromethoxybenzene were placed in 100 ml of 1,3-bistrifluoromethylbenzene and chlorine was then introduced at 100° C. under UV irradiation. A further 20 g of difluoromethoxybenzene were metered in over a period of 1 hour. When the chlorine uptake had ended, the mixture was purged with nitrogen and then distilled to give 35.5 g of chlorodifluoromethoxybenzene (boiling point: 144° C., refractive index nD20 : 1.4479).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH2:32]([OH:35])[CH2:33][CH3:34].[H-].[Na+]>C(#N)C>[CH2:32]([O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:28]([F:30])([F:29])[F:31])[CH2:33][CH3:34]
Reactant: CCCO
Reactant: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1C(F)(F)F
Temperature: 70 °C

Procedure:
(4-Fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (22 mg, 0.051 mmol), nPrOH (12 μL, 0.15 mmol), and NaH (60%, 6.1 mg, 0.15 mmol) were combined in acetonitrile (1 mL) and the reaction mixture was heated at 70° C. for 1 h. The reaction mixture was filtered and purified by reverse phase HPLC to provide (4-propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 470.2, found 471.2 (M−1)−; Retention time: 2.83 minutes (4 min run).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH2:20][CH:21]=O>C(O)(C)C>[F:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]3[N:7]([CH:20]=[CH:21][N:1]=3)[CH:6]=2)[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][CH3:15])=[O:13]
Reactant: O=CCCl
Reactant: CNC(=O)c1ccc(-c2cnc(N)nc2)cc1F
Solvent: CC(C)O
Product: CNC(=O)c1ccc(-c2cnc3nccn3c2)cc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzamide (123 mg, 0.5 mmol) and chloroacetaldehyde (0.318 mL, 2.5 mmol) in isopropyl alcohol (4 mL) was stirred at 90° C. for 4 h. The solvent was removed under vacuum and the residue was triturated with ethyl acetate and hexanes. The solid formed was collected and dried under reduced pressure to give the desired product (120 mg, 88.8%). LCMS: (M+H)=271.0.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1Cl
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)c(Cl)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 37.7 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidine (295 mg, 1.0 mmol) as crude materials, generated 98 mg title compound, yield was 38%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39](Cl)=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:23])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cc(C)n(C)n2)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (0.62 mmol) in acetonitrile (5 mL), was treated with potassium carbonate (1.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (0.68 mmol), before being heated to 120° C. in a microwave reactor for 4.5 hours. The mixture was evaporated in vacuo, before being partitioned between DCM (20 mL) and water (20 mL). The organics were evaporated in vacuo then chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (160 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11]Cl)[CH:9]=[CH:10][C:4]=2[O:3]1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Reactant: CC1Cc2cc(CCl)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1cccc(OCc2ccc3c(c2)CC(C)O3)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
2.8 g of 2,3-dihydro-2-methyl-5-benzofuranylmethyl chloride and 3.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was dried off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.7 g of Compound No. 46 shown in Table 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1

Procedure:
The second step involves treating a stirred solution of ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate in tetrahydrofuran-methanol with 6N aqueous sodium hydroxide solution at room temperature for 24 hours. Most of the tetrahydrofuran-methanol were removed by distillation under reduced pressure and the aqueous solution was acidified with 6N hydrochloric acid to obtain a solid which was filtered, washed with water and ether, then air dried, followed by drying in vacuo to obtain 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([F:12])[CH:4]=1>C(O)C.[Pd]>[F:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(F)c1
Yield: 98.5 %

Procedure:
A solution of 3-fluoro-4-nitrophenyl methyl ether (28.1 g, 164 mmol) in ethanol (200 mL) was hydrogenated with palladium on charcoal. The reaction mixture was filtered through Kieselguhr and evaporated under vacuum to afford the product as an oil (22.8 g, 98%); MS (+ve ion electrospray) m/z 141 (MH+).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[O:9])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Nicotinoyl chloride hydrochloride (286 mg, 1.61 mmol, 1.0 eq) was added at room temperature to a stirred solution of (S)-3-amino-1-N-BOC-pyrrolidine (300 mg, 1.61 mmol, 1.0 eq) in CH2Cl2 (9 mL), followed by triethylamine (337 μL, 2.42 mmol, 1.5 eq). After stirring overnight at room temperature, the reaction mixture was extracted and the organic layer was dried over Na2SO4, filtered and evaporated to afford 457 mg of the expected compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[N:7]=[C:6]2[C:8](=[O:10])[O:13][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(C(=O)O)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(n1)C(=O)OC2=O
Temperature: 100 °C

Procedure:
In a 100 ml round-bottomed flask 6-methyl-2,3-pyridinedicarboxylic acid (10 g, 55.2 mmol) and acetic anhydride (26 ml, 276 mmol) were added and heated at 100° C. under nitrogen for 5 hours. After this time the volatiles were removed under vacuum to give the title compound D32 (8.2 g) as a slightly brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, 1 H), 7.82 (d, 1 H), 2.73 (s, 3 H).