Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCCCO)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Into a room temperature, stirred solution of (S)-2-(4-hydroxybutyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.344 g, 0.95 mmol), and MeI (0.179 mL, 2.87 mmol) in DMF (5 mL) add NaH (0.042 g, 1.05 mmol, 20% in mineral oil). Stir overnight. Dilute the mixture with 75% brine (50 mL) and extract with EtOAc (3×100 mL). Concentrate the organic layers under reduced pressure, dilute with EtOAc (40 mL) and wash with 75% brine (5×25 mL). Dry the organic layer over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 20% to 98% EtOAc in hexanes. Combine the purified fractions, concentrate under reduced pressure and place under vacuum to give the title compound: yellow tar (0.209 g), mass spectrum (m/e):373.13 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=1)(=[O:4])[CH2:2]C.CO.C[N:16]([CH3:19])C=O>>[N:16]1[C:19]2[CH:11]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][C:2]=1[C:1]([NH:5][C:6]1[CH:12]=[CH:11][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: CCC(=O)Nc1ccc(N)cc1
Solvent: CO
Product: O=C(Nc1ccccc1)c1nc2ccccc2[nH]1

Procedure:
14.4 g (0.05 mol) of dibenzimidazo(1,2a,1',2'-d)tetrahydropyrazine-6,13-dione and 30 g (0.18 mol) of 4-propionylaminoaniline are heated under reflux in 70 ml of dry dimethylformamide for 3 hours. After cooling down, about 700 ml of methanol are added. The precipitated solid is filtered off with suction and washed with methanol and dried to leave 20.7 g of the benzimidazole-2-carboxanilide of the formula ##STR93## Melting point 289°-291° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([NH:1][C:29]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=4)=[O:30])[CH:3]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(C)c(N)c3)ccc2n1
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4nccn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (150 mg, 0.50 mmol) in N,N-dimethylformamide (3.0 mL) were added 1-methyl-1H-imidazole-2-carboxylic acid (127 mg, 1.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (290 mg, 1.51 mmol) and 1-hydroxybenzotriazole (205 mg, 1.51 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate/ethanol to give the title compound (115 mg, 56%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
4-Chloropyridine-2-carbonitrile 19B (2.0 gr, 14.44 mmol) was dissolved in 35 ml of dioxane. The solution was added with cesium carbonate (6.8 gr), [4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 3.3 gr) and palladium acetate/XPhos (80 mg/280 mg) under argon atmosphere. The mixture was stirred at 100° C. for 4 hours. The reaction is filtered through a pad of celite, concentrated and crystallized from diethyl ether/petroleum ether to give a beige solid (3.2 gr, 12.85 mmol, yield: 89%) 1HNMR (DMSO, 400 MHz) δ 7.92 (2H, dd, J=8.0 Hz), 8.12 (3H, m), 8.51 (1H, dd), 8.39 (1H, dd, J=5.2 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH:20]O.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
A mixture of 20 mg (0.080 mmol) of 3-(4-methoxyphenyl)-1H-indazole-5-carbonitrile, 0.428 mL of 95% denatured ethanol, 0.021 mL of H2O, 0.32 mL of 30% aqueous hydrogen peroxide (aq. H2O2) and 0.032 mL of 6.0 N aq. NaOH (0.192 mmol, 2.4 equiv.) was heated at 50° C. for 3 h, and then acidified to pH=6.0 with 0.052 mL of 6.0 N 10 aq. HCl. The mixture was extracted with 2× EtOAc. The combined organics were washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated affording the title compound (8.9 mg, 41.6% yield): 1H NMR (CDCl3/DMSO-d6) δ 12.5 (br s, 1H), 8.60 (s, 1H), 7.95 (d, 2H), 7.85 (d, 2H), 7.55 (d, 1H), 7.05 (d, 2H), 3.89 (s, 3H); ES-MS (m/z) 268 [M+1]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].CCN(CC)CC.[Cl:30][C:31]1[CH:32]=[N+:33]([O-:60])[CH:34]=[C:35]([Cl:59])[C:36]=1[CH2:37][C@H:38]([O:49][C:50]([C:52]1[S:53][C:54]([CH:57]=O)=[CH:55][CH:56]=1)=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[Cl:59][C:35]1[CH:34]=[N+:33]([O-:60])[CH:32]=[C:31]([Cl:30])[C:36]=1[CH2:37][C@H:38]([O:49][C:50]([C:52]1[S:53][C:54]([CH2:57][NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:5](=[O:6])[O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[CH:55][CH:56]=1)=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3cccc(F)c3)s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A suspension of (R)-quinuclidin-3-yl 2-amino-2-(3-fluorophenyl)acetate bis hydrochloride salt (0.176 g, 0.500 mmol) in EtOAc (5 mL) was added with Et3N (0.150 mL, 1.10 mmol). The reaction mixture was stirred at room temperature for 2 h. The precipitate obtained was filtered, washed with EtOAc (˜5 mL) and the solvent was removed in vacuo. This residue was dissolved in CH3CN (5 mL) and to the solution was added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.220 g, 0.456 mmol) followed by acetic acid (0.026 mL, 0.456 mmol). The reaction mixture was stirred at room temperature for 20 h. NaBH(OAc)3 (0.265 g, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The excess solvent was removed in vacuo and the residue was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO3 solution (20 mL). The organic layer was washed with saturated brine (2×15 mL), separated and filtered through a phase separator cartridge and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound (1:1 mixture of diastereoisomers) as a pale yellow solid (200 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)[N:6]=1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g, Reference Example 55) and p-toluene sulfonic acid (144 mg) in chloroform (30 ml) at 0° C. was treated with 3,4-dihydropyran (1.04 ml) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (40 ml) and water (3×40 ml). The combined aqueous layers were extracted with dichloromethane (3×60 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to yield 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (2.23 g) as a viscous brown oil. LC-MS (Method H): RT=2.79 minutes, 278.21 (M+H+ Na)+.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[Li+].[C:9]([NH:12][NH2:13])([NH2:11])=[NH:10].Cl.C(O)C>O>[C:9]([NH:12][N:13]=[C:3]([CH3:5])[CH2:2][C:1]([OH:7])=[O:6])(=[NH:10])[NH2:11]
Reactant: N=C(N)NN
Reactant: CC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CC(CC(=O)O)=NNC(=N)N
Reaction time: 24 h

Procedure:
Lithium acetoacetate (0.655 g) in 2 ml water was treated with 0.665 g aminoguanidine HCl in 1.33 ml water. The solution was heated to reflux over 30 minutes and then allowed to cool. Ethanol (10 ml) was added and the mixture was stored at -20° C. for 24 hrs., then at 4° C. for 24 hrs. The mixture was allowed to reach room temperature and filtered. The filtrate was concentrated to a paste and triturated with 5 ml ethanol. Filtration and washing with ethanol gave 0.522 to the hydrazone as a microcrystalline powder, melting point 138.6°-140° C.
Reaction SMILES: [ClH:1].[Cl:2][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Cl.[NH3:15]>CO.CCOCC>[ClH:2].[ClH:1].[NH2:15][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: N
Reactant: Cc1cnc2c(c1)CCCC2Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1cnc2c(c1)CCCC2N

Procedure:
The 8-chloro product of Example 2 (17 g.) was dissolved in methanol saturated with ammonia (400 ml.) and heated at 80° in a stainless steel bomb for 24 hours. The solvent was removed in vacuo and the residual oil triturated with anhydrous ether (3 × 50 ml.) and the triturates discarded. The oily solid was dissolved in water and the pH adjusted to 9.0 with sodium carbonate and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (5.5 g.). A sample (500 mg.) was dissolved in anhydrous ether (25 ml.) and the solution treated with excess ethereal hydrogen chloride and the resultant solid recrystallised from methanol-ether to give 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline dihydrochloride quarter hydrate as colourless needles m.p. 210° C. (Found: C,50.5;H,6.9; N,11.6. C10H14N2.2HC1. 1/4H2O requires: C,50.2; H, 7.1; N, 11.7%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: N
Product: Oc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-fluoro-4-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.09 (t, J=8.7 Hz, 1H), 7.63 (ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.86-7.93 (m, 2H), 8.53 (dt, J=7.9, 2.0 Hz, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 258 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: NC1CCCCC1
Solvent: CCO
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and cyclohexylamine in ethanol. EI-MS m/e (%): 283 (M+, 22), 282 ([M—H]+, 20), 240 ([M—C2H5]+, 16), 226 ([M—C4H9]+, 36), 201 ([M—C6H10]+, 100).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC)C>>[CH2:5]([N:1]([CH2:2][CH3:3])[CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)[CH3:4]
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCNCC
Product: CCN(CC)C[C@@H]1CCCN1

Procedure:
N,N-Diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine was synthesized as described for (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine starting with N,N-diethylamine instead of pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2=[O:31].C(=O)(O)[O-].[K+].Br[CH2:38][C:39]1[O:40][C:41](=[O:45])[O:42][C:43]=1[CH3:44]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:38][C:39]3[O:40][C:41](=[O:45])[O:42][C:43]=3[CH3:44])[CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2=[O:31]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(c1ccccc1)S2
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(Cc5oc(=O)oc5C)CC4)c(F)cc3c1=O)C(c1ccccc1)S2
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
Ethyl 6-fluoro-4-oxo-1-phenyl-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.0 g) and 0.82 g of potasium bicarbonate were suspended in 50 ml of N,N-dimethylformamide, 1.58 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the mixture was poured over into ice water and the crystals separated out therefrom were collected by filtration. They were then dissolved in chloroform, the solution was washed with water, and evaporated/dried in vacuo. The resulting oily residue was purified by a column chromatography (silica gel/methanolchloroform [1:50]) to give 2.47 g of desired product, mp, 223°-226° C. (decompn.).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[Cl:1][C:2]1[N:11]=[C:10]([O:16][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(Cl)nc(OC)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A solution of 2,4-dichloro-6-methoxyquinazoline (0.33 g) in methanol (5 mL) was added sodium methoxide (0.086 g), and the mixture was stirred at room temperature for 6 h. Water was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol=50:1) to obtain 2-chloro-4,6-dimethoxyquinazoline (0.20 g).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[S:2].[Na+:6].[Na+].[I-].[Na+].Cl[CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24].O>C(O)C>[S:1]([O-:5])([S:2][CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24])(=[O:4])=[O:3].[Na+:6]
Reactant: O=S([O-])([O-])=S
Reactant: Cc1ccc2c(c1)N(CCCl)C(C)CO2
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)N(CCSS(=O)(=O)[O-])C(C)CO2

Procedure:
Sodium thiosulfate (0.2 m), sodium iodide (1 g), N-(2-chloroethyl)-3,6-dimethyl-2H-1,4-benzoxazine, water (150 ml), and ethanol (75 ml) were mixed and heated at reflux for 3 hrs. The alcohol was distilled off and the reaction mixture was cooled. The product, a white solid, was collected by filtration and dried in air. The yield was essentially quantitative. Preparation of the Dyes
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24][S:23](=[O:26])(=[O:25])[CH2:22]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:21]1([NH:20][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:22][S:23](=[O:25])(=[O:26])[CH2:24]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (19.3 mg, 28%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH4+]=[S:12].C(N(CC)CC)C>N1C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[S:12])[NH2:5]
Reactant: N#Cc1cc(F)ccc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A stirred solution of 2,5-difluorobenzonitrile (25 g, 180 mmol) in pyridine (90 mL) was treated with 20 wt % ammonium sulfide in water (67.4 mL, 198 mmol) and triethylamine (27.4 mL, 198 mmol). The reaction mixture was stirred at 50° C. for 5 hr until the reaction was complete. After cooling to room temperature, the mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, then washed with H2O (×3), brine (×3), then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification on silica gel column (20% EtOAc in hexanes) to afford 2,5-difluorobenzothioamide as yellow solid (31.0 g, 99%). 1H NMR (CDCl3, 300 MHz): δ 7.12 (m, 2H), 7.90 (br, 2H), 8.08 (m, 1H). LC/MS (uplc): MH+174.0, 0.64 min.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14]>ClCCl>[CH:1]([NH:14][C:13]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=1[CH3:11])=[O:3]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c(NC=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,4,6-trimethylaniline (13.521 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with hot diethyl ether (2×50 mL) to afford N-formyl-2,4,6-trimethylaniline 8c1 as a white solid (11.42 g, 70%). 1H NMR (CDCl3, 300 MHz): δ=8.39-8.03 (m, 1H, CHO), 7.26-6.91 (m, 2H), 6.75 (broad s, 1H, NH), 2.29-2.21 (m, 9H); 13C{1H} NMR (CDCl3, 75 MHz): δ=165.48, 160.05, 137.75, 137.61, 135.37, 135.16, 130.92, 130.74, 129.53, 129.16, 21.15, 21.12, 18.84, 18.64; HRMS (FAB+) calculated for C10H14NO [M]+ 164.1075, observed 164.1116. 1 (a) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liehigs Ann./Recited 1997, 365-374. (b) J. Liebscher, Methoden der Organischen Chemie (Hauben-Weyl) 4th ed. (Ed.: E. Schaumann), Georg Thieme Verlag, New York, 1994 Band E 8b, Heratrene III/Part 2, p. 48. (c) Hromatka, O. U.S. Pat. No. 2,160,867, 1939.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:32][C:33]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([N:35]1[CH2:36][CH2:37][C:33]([F:38])([F:32])[CH2:34]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1-(tert-Butoxycarbonyl)-4-oxo-L-proline (6.88 g, 30 mmol), HOBt (4.46 g, 33 mmol), EDC (6.326 g, 33 mmol), and 3,3-difluoropyrrolidine hydrochloride (4.52 g, 31.5 mmol) were dissolved in 100 mL of dichloromethane and the reaction mixture was cooled to 0° C. in an ice bath before adding TEA (8.4 mL, 60 mmol). The reaction mixture was then allowed to warm to RT. After stirring overnight, saturated sodium bicarbonate (100 mL) was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (Biotage® Flash 40M, eluting with 1:10 dichloromethane:hexanes) to afford the title compound 7.85 g (82% yield). MS (EI) m/z 319.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:12][C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)c(C)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(CBr)cc1F
Temperature: 88 °C
Reaction time: 18 h
Yield: 37.1 %

Procedure:
To methyl 2,5-difluoro-4-methylbenzoate (Preparation 26, 55 g, 0.29 mol) in carbon tetrachloride (0.4 L) was added N-bromosuccinimide (52.6 g, 0.29 mol) and dibenzoyl peroxide (1 g, 3.5 mmol) and heated at 88° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and allowed to stand for 18 hours, then washed with water (400 mL), brine (100 mL), dried over sodium sulphate and concentrated in vacuo. The resulting solid was triturated with n-heptane (120 mL) and recrystallised from hot n-heptane (50 mL) to yield the title compound as a pale yellow solid (28.5 g, 36%).