Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: NCc1ccccn1
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-methoxybenzyl chloride (1.50 g, 9.5 mmol) and 2-(Aminomethyl)pyridine (5.18 g, 47 mmol) were dissolved in 800 mL CH3CN. To this solution was added potassium carbonate (1.324 g, 9.5 mmol) and the mixture was stirred at room temperature for three days. The solvent was evaporated, and the residual oil was dissolved in CH2Cl2 (75 mL) and extracted with water (75 mL×3). The combined CH2Cl2 layers were reduced in volume, and the resulting yellow-orange oil was purified by silica gel chromatography eluting with CH2Cl2, followed by a 3% (NH3)MeOH/97% CH2Cl2 solution (62%). 1H NMR (CDCl3) δ 8.520 (dd, 1H, Ar), 7.600 (m, 1H, Ar), 7.335 (d, 1H, Ar), 7.27 (d, 1H, Ar), 7.211 (t, 1H, Ar), 7.113 (m, 1H, Ar), 6.895 (t, 1H, Ar), 6.832 (d, 1H, Ar), 3.921 (s, 2H, —CH2—), 3.864 (s, 2H, —CH2—), 3.800 (s, 3H, —OCH3), 3.043 (s(br), 1H, —CH—). Mass Spec.=229.13 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:14][CH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 80 °C
Yield: 55.2 %

Procedure:
D5 (2 g, 10.97 mmol), N-bromosuccinimide (2.94 g, 16.46 mmol) and benzoyl peroxide (0.57 g, 1.65 mmol) were dissolved in carbon tetrachloride (40 ml) and heated to 80° C. for 3 h. The mixture was diluted with EtOAc (60 ml) and washed with saturated NaHCO3 solution and brine (100 ml each), dried (Na2SO4) and concentrated. Purification by column chromatography on silica (0-50% diethyl ether\40-60 pet. ether gradient) gave the title compound as a yellow oil (1.58 g). δH (CDCl3) 1.65 (9H, s), 4.49 (2H, s), 6.47 (1H, d), 8.03 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(C(/C=C\c2ccc(Br)cc2)SC(/C=C\c2ccc(Br)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-bromostyryl 4-chlorobenzylsulfide. The title compound was obtained in 87% yield following oxidation. 1HNMR (CDC13) δ4.58 (2H, s), 6.72 (1H, d, JH,H=12.08), 7.15-7.68 (8H aromatic+1H ethylenic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-methoxypropylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(3-methoxypropyl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][Cl:32].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:29][CH2:30][CH2:31][Cl:32])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.02 %

Procedure:
To a suspension of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (1.83 g), K2CO3 (2.21 g), in DMF (20 mL) was added 1-bromo-3-chloropropane (1.90 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (2.11 g, 91.02%).
Reaction SMILES: C[N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:9]=2/[CH:10]=[C:11]2/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/2)[CH2:4]1.O=C[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[Na].O>C(Cl)Cl>[O:16]=[C:14]1[NH:13][C:12](=[O:17])/[C:11](=[CH:10]/[C:9]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:8]=2[N:5]2[CH2:6][CH2:7][CH:3]([NH:2][CH2:26][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:4]2)/[S:15]1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(N(C)C)C2)cc1OC
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(NCCNC(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5Z)-5-{2-[3-(dimethylamino)pyrrolidin-1-yl]-4,5-dimethoxybenzylidene}-1,3-thiazolidine-2,4-dione (Example 52) (120 mg, 0.31 mmol) and tert-butyl 2-oxoethylcarbamate (198 mg, 1.24 mmol) in CH2Cl2 (20 mL) were heated to reflux for 15 min followed by the addition of sodium triacetoxyhydroborate (65.9 mg, 0.31 mmol). The reaction mixture was refluxed overnight before being allowed to cool to ambient temperature. Water (˜0.5 mL) was added and the mixture was allowed to stir for 15 min before being loaded onto a silica gel column which was eluted with ethyl acetate/hexane (10:1) to yield the title compound as an orange solid as (60.0 mg, 39.2%); m/z 493.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:23][C:24]1[C:25]([NH2:48])=[C:26]([O:39][CH2:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([N:23]1[C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])[CH:27]=[C:26]([O:39][CH2:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[C:25]=2[N:48]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNc1cc(OCCCN(CC)CC)cc(OCCCN(CC)CC)c1N
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2c(OCCCN(CC)CC)cc(OCCCN(CC)CC)cc21
Yield: 31.9 %

Procedure:
This compound was prepared according to General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (300 mg) and N1-Butyl-3,5-bis-(3-diethylamino-propoxy)-benzene-1,2-diamine (synthesized via General Procedures J1 and J2 and I) (200 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure (3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (100 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)C.O>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cc(Br)ccc12
Reaction time: 22 h

Procedure:
A solution of 10 g of 4-bromo-2-fluorobenzonitrile in 300 mL of ethanol is admixed with 7.29 mL of hydrazine hydrate. The reaction mixture is stirred for 22 hours at reflux and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 200 mL of distilled water. The suspended solid is isolated by filtration, washed with water and treated with suction. After drying under vacuum, 10 g of 6-bromo-3-amino-1H-indazole are obtained, whose characteristics are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2Cl)[CH2:7]3)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19]>CC(O)(C)C>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])[CH2:7]3)=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: ClC1=NC2CC(C2)c2ccc(Br)cc21
Solvent: CC(C)(C)O
Product: COC(CNC1=NC2CC(C2)c2ccc(Br)cc21)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 104.3 %

Procedure:
Into a 10-L 4-necked round-bottom flask was placed 5-bromo-8-chloro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene (260 g, 960.99 mmol, 1.00 equiv), 2-methylpropan-2-ol (6000 mL), and 2,2-dimethoxyethan-1-amine (600 g, 5.71 mol, 6.00 equiv). The resulting solution was stirred at 85° C. for 5 h, cooled to room temperature and concentrated under vacuum. The residue was washed with 2×500 mL water and extracted with 3×500 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum to afford 340 g (crude) of 5-bromo-N-(2,2-dimethoxyethyl)-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine as a black oil.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH:52][NH2:53])=[CH:47][CH:46]=1.Cl.Cl.Cl>CN(C=O)C>[CH2:51]([N:52]1[C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4](=[O:6])[NH:53]1)[C:48]1[CH:49]=[CH:50][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]n(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (0.5 g) in DMF (9 mL) was added TBTU (1.04 g) followed by N-ethyldiisopropylamine (2.3 mL). After 10 minutes benzylhydrazine.2HCl (0.63 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-benzyl-5-nitro-1,2-dihydro-indazol-3-one (0.26 g) as a yellow solid. MS (ESI−):268.3 ([M−H]−).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([O:27]C)=[O:26])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([OH:27])=[O:26])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 89.2 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzoyl}(hexyl)amino]-2-fluorobenzoate (170 mg; 0.33 mmol) in THF (7 mL) were added lithium hydroxide monohydrate (139 mg; 3.31 mmol) and water (3 mL). The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl (1N) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 147 mg (88.9%) of the title compound as a colorless solid. HPLC, Rt: 5.54 min (purity=98.4%), LC/MS: M−(ESI): 498.3. 1H NMR (MeOD) δ: 7.61 (m, 1H), 7.29 (d, J=7.9 Hz, 5H), 7.22 (d, J=7.9 Hz, 2H), 7.08 (d, J=7.9 Hz, 2H), 7.03 (s, 1H), 3.8 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 1.49 (q, J=7.4 Hz, 4H), 1.25 (m, 8H), 0.82 (m, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([N:25](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(N3CCOCC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(N3CCOCC3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 3-morpholino-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.066 g, 0.095 mmol) in 5 mL of DCM was treated with TFA (0.5 ml, 6.49 mmol). The reaction was stirred for 3 hrs at 50° C. The mixture was cooled to RT and was diluted with DCM (25 mL). The derived solution was washed with saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3×15 mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep 12 g, gradient elution 0-100% DCM: 100:10:1 DCM, MeOH, NH4OH) to provide 3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as a racemic mixture. Chiral separation provided (S)-3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine and (R)-3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine, both isomers as a white solid. MS m/z=432.3.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1ccc2c(c1)OC(C)O2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)O2
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
59.3 g of 2-methyl-5-acetamino-1,3-benzodioxole were nitrated at 15°-25° C. in 225 ml of glacial acetic acid by the dropwise addition of 27 ml of nitric acid in 95 ml of glacial acetic acid. After 30 minutes, the temperature rose spontaneously to 45° C. and the color of the mixture changed from yellow to red. The precipitated crystals were removed by filtration under suction and washed with methanol. There were obtained 64.4 g (88.5% of theory) of 2-methyl-5-acetamino-6-nitro-1,3-benzodioxole of melting point 112°-113° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (795 mg, 3.68 mmol) in DCM (20 mL) was added triethylamine (1.53 mL, 11.04 mmol). The resulting mixture was cooled to 0° C. before the dropwise addition of chloroacetyl chloride (325 μL, 4.05 mmol). The mixture was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil which was a mixture of rotamers (710 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[CH2:22]([O:16][C:15](=[O:17])[CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:23]
Reactant: CCO
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (0.405 g, 1.37 mmol) in EtOH (4 mL) was treated with thionyl chloride (0.2 mL, 2.73 mmol) and the reaction was stirred at room temperature until no starting material was seen by analytical TLC. After basic workup the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[As](=O)(O)(O)O.S(=O)(=O)(O)O.N.O[CH2:26][CH:27]([CH2:29]O)O>C(O)(=O)C.O>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[C:10]2[C:2]=1[N:1]=[CH:29][CH:27]=[CH:26]2)([OH:6])=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: OCC(O)CO
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2cccnc12
Yield: 83.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (4 g, 22 mM), glycerol (8 g), arsenic acid (80% in water) (20 g), and sulphuric acid (65%) (36 ml) was heated at reflux for 3.5 hours. After addition of water (100 ml), the pH was adjusted to 8 with concentrated ammonia and then to 3.5 with acetic acid. The resulting precipitate was filtered and dried to give 8-carboxy-6-nitroquinoline (4 g; 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[N:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[C:11]([CH2:16][O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnc(Cl)c(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.9 %

Procedure:
To a solution of (5-(benzyloxy)-6-chloropyridin-3-yl)methanol (1.76 g) and tert-butyldimethylchlorosilane (1.59 g) in DMF (10 mL) was added imidazole (960 mg), and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: OCCCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Yield: 63.8 %

Procedure:
(Navalokina, R. Et al J. Org. Chem. USSR (Engl. Trans.), 1980, 16, 1382–1386.2) Ramalingam, K. U.S. Pat. No. 4,864,051, 1989.). A 250 mL round bottom flask was charged with ZnCl2 (68.14 g, 0.5 mole) which was then fused by heating under vacuum. After returning to room temperature the material was placed under an atmosphere of N2. To this was added acetone cyanohydrin (45.66 mL, 0.5 mole) followed by 2-chloroethanol (50.24 mL, 0.75 mole) and the mixture placed in a preheated oil bath (60° C.). After stirring for 18–20 h at 60° C., the reaction mixture was cooled, diluted with water (300 mL) and washed with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. Purification was accomplished by vacuum distillation (10 mm Hg) using a vigreux column. The fraction boiling between 65–75° C. was collected to afford the desired product as a colorless oil (47.1 g, 63.8% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 3.85 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.60 (6H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.Cl.[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:21]=[CH:20][C:19]([C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[C:18]([CH3:22])[CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of anhydrous aluminum chloride (19.5 g) dispersed in m-xylene (150 ml) was added dropwise 4-fluorobenzoyl chloride (21.1 g) under ice-cooling. The mixture was stirred at 0-10° C. for 3 hr and poured into 6N hydrochloric acid. The reaction mixture was partitioned and the obtained organic layer was washed successively with water, 10% aqueous sodium hydroxide solution and water. The solvent was evaporated to give a 96:4 mixture (30.2 g, 99%) of 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene and 1,3-dimethyl-2-(4′-fluorobenzoyl)benzene as pale-yellow oil. 1,3-Dimethyl-4-(4′-fluorobenzoyl)benzene
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].N12CCCN=C1CCCCC2.CC1C=CC([C:24]2[C:25]([F:53])=[C:26]([CH:30]=[C:31]([Cl:52])[C:32]=2[O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:49])[F:48])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:27]([O-])=[O:28])=CC=1>C(#N)C>[Cl:52][C:31]1[C:32]([O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:48])[F:49])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)=[CH:24][C:25]([F:53])=[C:26]([CH:30]=1)[C:27]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: Cc1ccc(-c2c(F)c(C(=O)[O-])cc(Cl)c2Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Methanesulphonamide (89.54 mg, 0.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1.03 mmol) were added to 4-methylphenyl-5-chloro-4-(6-(2,2,3,3-tetrafluoropropoxy)-5-(trifluoromethyl)pyridin-3-yloxy)-2-fluorobenzoate (Preparation 263, 475 mg, 0.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred for 18 hours at room temperature. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase chromatography (acetonitrile/water both with 0.1% formic acid) to give the title compound as a white solid (303 mg, 55%).