Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@H:13]1[O:35][C@H:34]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@H:14]1[O:15]C(=O)C1C=CC=CC=1)(=O)C.[Sn](Cl)(Cl)(Cl)Cl>C(#N)C>[C@@H:13]1([N:1]2[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:35][C@H:34]([CH2:36][OH:37])[C@H:24]([OH:25])[C@H:14]1[OH:15]
Reactant: CC(=O)O[C@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)c(=O)n1

Procedure:
One equivalent of cytosine is condensed with one equivalent of 1-O-acetyl-2,3,5-tri-O-benzoyl-α-D-xylofuranose at ambient temperature, in anhydrous acetonitrile, in the presence of tin tetrachloride, SnCl4 (2 equivalents); the compound obtained is purified by chromatography on a silica column and debenzoylated using a methonal solution saturated with ammonia gas. This gives 1-(β-D-xylofuranosyl)-cytosine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:14])([F:12])[F:13])=[CH:9][N:8]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Clc1nccc2ccccc12
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(-c2nccc3ccccc23)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 17 h
Yield: 87.3 %

Procedure:
1.04 g (5 mmol) of 3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrrole and 0.818 g (5 mmol) of 1-chloroisoquinoline are added to 1.73 g (12.5 mmol) of potassium carbonate suspended in 10 mL of dimethyl sulphoxide at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 17 hours at a temperature in the region of 110° C., the reaction mixture is cooled and then diluted with 30 mL of water. The solid formed is filtered off and washed with water and then oven-dried under reduced pressure (2.7 kPa), giving 1.46 g of 3-ethoxycarbonyl-4-trifluoromethyl-1-(isoquinolin-1-yl)-1H-pyrrole in the form of cream-colored crystals. IR spectrum (KBr), 3159; 2983; 2937; 1721; 1628; 1555; 1534; 1502; 1405; 1343; 1290; 1272; 1215; 1179; 1151; 1135; 1120; 1035; 831; 809; 755; 679 and 674 cm−1. Mass spectrum (EI) m/e 334 (M+.), m/e 289.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:15]([OH:17])=[O:16])[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(OC(C)(C)C)(=O)C>[NH2:1][CH2:2][C@@H:3]([C:15]([O:17][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:16])[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reaction time: 96 h

Procedure:
2.5 ml of concentrated HClO4 is added without exceeding 5° C. to a suspension of 5 g of N-alpha-[(phenylmethoxy)carbonyl]-L-alpha,beta-diaminopropionic acid 10-1 (alternative nomenclature: (3-amino-N-[(phenylmethoxy)carbonyl]-L-alanine) in 25 ml of tertbutyl acetate cooled down to 0° C., the temperature of the reaction medium is allowed to rise to 20° C. and agitation is carried out for 4 days at 20° C. The reaction medium is poured into a sodium bicarbonate/ice solution (300 ml/200 ml), followed by extracting with ethyl acetate, filtering, decanting, drying the organic phase, evaporating under reduced pressure until a dry extract is obtained corresponding to the expected product (3.2 g) which is used as it is in the following reaction.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[C:9]([NH:17][C:18]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[CH:33]=[CH:32]3)[CH:25]=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(OCC)(=O)C.O.CO>[C:9]([NH:17][C:18]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[CH:33]=[CH:32]3)[CH:25]=[CH:24][C:19]=1[C:20]([OH:22])=[O:21])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Oc2ccc3c(ccn3C)c2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ccc2cc(Oc3ccc(C(=O)O)c(NC(=O)c4ccccc4)c3)ccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.094 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 1.5 mL of dioxane and 1.5 mL of methanol containing 50 mg of methyl 2-(benzamido)-4-(1-methyl-1H-indol-5-yloxy)benzoate at room temperature, stirred at 50° C. for 1 hour, and 0.031 mL of 2.0 mol/L aqueous sodium hydroxide was added at the same temperature and then stirred at 50° C. for 30 minutes. After the reaction mixture was cooled to room temperature, water was added and pH was adjusted to pH 3.5 with 1.0 mol/L hydrochloric acid and ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with water and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 37 mg of 2-(benzamido)-4-(1-methyl-1H-indol-5-yloxy)benzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:17]([N+:22]([O-:24])=[O:23])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:4]2[C:3]=1[N:29]([CH:26]1[CH2:28][CH2:27]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
The ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitro- benzoyl)-3-ethoxyacrylate prepared in the previous step was dissolved in 200 ml of t-butanol and treated with 5.0 g (88 mmol) of cyclopropylamine. The reaction mixture was warmed to 45° C. and stirred for three hours at that temperature. The solution was then cooled to room temperature and treated with a slurry of 9.4 g (84 mmol) of potassium t-butoxide in 50 ml of t-butanol. The mixture was stirred at 60° C. for five hours; the suspension was filtered, and the solid was washed with water and ether to give 21.7 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:11]=3[C:12]=2[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)O)=[CH:4][CH:3]=1.C>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:11]=3[C:12]=2[CH2:13][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2oc3cc(O)ccc3c2C(O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: C
Product: Oc1ccc(-c2oc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 52.4 %

Procedure:
550 mg (1.2 mmol) of the product of Example 11 was reduced to the methane by the method described in Example 2. This yielded 270 mg of the title compound as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (17 mg, 0.057 mmol), N3-(3-Fluoro-phenyl)-1H-indazole-3,5-diamine (14 mg, 0.057 mmol) and PyBroP (27 mg, 0.057 mmol) in methylene chloride (1 ml) was added diisopropylethylamine 20 μL. The mixture was allowed to stir overnight at room temperature and the titled compound (7.5 mg, 25%) was purified with HPLC. MS (ESI) m/z=493 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ8.02 (s, 1H), 7.38-7.30(m, 3H), 7.23-7.15 (m, 2H), 7.01-6.99 (m, 2H), 6.91-6.86 (m, 2H), 6.58-6.53 (m, 1H)
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: NN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Solvent: O
Solvent: CCO
Product: NNc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A mixture of 6.1 g (25 mmol) of 2,3-dichloro-6-nitroquinoxaline and 2.75 g (55 mmol) of hydrazine hydrate in 150 ml of ethanol was stirred at room temperature over night. The precipitate was isolated and washed with water, cold ethanol and ether to give 5.67 g (95%) of crude product.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:24])[C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(6-fluoro-3-methyl-1,2-benzisoxazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 9.12 mmol) and potassium carbonate (2.52 g, 18.2 mmol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (2.58 g, 18.2 mmol), stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid which is recrystallized from a methylene chloride/hexanes solution to give the title product as a white solid (mp 158-159° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: ClCc1ccc(Cl)cc1
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
Reaction of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione with 4-chlorobenzyl chloride according to the procedure of Example 4, Step A (with reaction time shortened to 4.5 hours) gave a 90% yield of the title compound as an oil, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB m/e 417 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[O:34]=[C:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][NH2:43]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:43][CH2:42][CH2:41][CH2:40][N:36]1[CH2:37][CH2:38][CH2:39][C:35]1=[O:34])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
In 100 ml of THF was dissolved 9.97 g of compound (29) and after adding slowly thereto 4.45 g of triethylamine and then 6.01 g of isobutyl chloroformate under ice-cooling, the reaction was performed under ice-cooling. To the reaction mixture was slowly added 11.37 g of 3-(2-oxo-1-pyrrolidinyl)-propylamine and then the reaction was performed for one hour under ice-cooling. Precipitates were filtered off, the filtrate was concentrated, and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with ethyl acetatemethanol (4:1), 4.43 g of (S)-1-benzyloxycarbonyl-N-[3-(2-oxo-pyrrolidinyl)propyl]-2-pyrrolidine carboxamide (99) was obtained.
Reaction SMILES: ClC(OCC)=O.C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH2:21][CH3:22])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH2:21][CH3:22])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: CCC1c2ccc(OC)cc2C2CNCC12
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCC1c2ccc(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
Ethyl chloroformate (0.16 mL, 1.65 mmol) was added to a solution of 5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 48, Step B) (0.24 g, 1.1 mmol) in CH2Cl2 (6 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was quenched with aqueous HCl solution (20 mL, 1.0 M) and the product was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford 40 mg (13%) of the subtitle compound. MS calculated for C17H23NO3+H: 290, observed: 290.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:9]#[N:10].[K+].S(=O)(=O)(O)O>O>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:8])[C:9]#[N:10])=[CH:3][CH:4]=1
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 ml four-neck round bottom flask was equipped with a magnetic stirring bar, water condenser, addition funnel and drying tube. The glassware was dried and to this was charged 21.2 grams (0.2 mole) benzaldehyde and 19.5 grams (0.3 mole) potassium cyanide dissolved in 70 ml of water. The reaction flask was cooled to 10°-15° C. using a water/ice bath. To this was added 70 ml of 40% sulfuric acid over a 60 minute period. After the addition was complete, the reaction was allowed to warm to room temperature and stir for an additional two hours. At the end of this time the reaction mixture was extracted with carbon tetrachloride (3×75 ml), washed the combined carbon tetrachloride layers with water (2×50 ml), dried the carbon tetrachloride layer with anhydrous magnesium sulfate, filtered and concentrated to yield benzaldehyde cyanohydrin.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].N[CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][CH2:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: NCCCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CNCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of 2-nitrobenzyl amine (17 g, 78 mmol) in DMF (50 mL) was cooled to 0° C. and treated dropwise with a solution of 3-amino-1-propanol (50 mL, 0.65 mol) in DMF (150 mL) over 0.5 hours. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature for 2 hours, and evaporated to a red oil. The crude product residue was purified by flash chromatography (SiO2, 10% 0.5 M NH3-methanol/dichloromethane) to afford 3-[(2-nitrobenzyl)amino]propan-1-ol (16 g, 98%) as a yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:32][CH2:31]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12.C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:31][CH2:32]5)[CH2:26][N:27]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 109B (75 mg, 0.149 mmol) in 2 mL N,N-dimethylformamide was added diisopropylethylamine (0.130 ml, 0.744 mmol) followed by methanesulfonyl chloride (0.017 ml, 0.223 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate. The organics were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was triturated with ethyl acetate, filtered and dried over high vacuum to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.85-1.12 (m, 4H) 1.99 (s, 2H) 2.86-3.02 (m, 3H) 4.55 (s, 2H) 6.90 (d, J=8.33 Hz, 1H) 7.13 (d, J=1.59 Hz, 1H) 7.44-7.94 (m, 6H) 9.16 (s, 1H) 10.84 (s, 1H). MS (ESI+) m/z 582.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Reaction time: 18 h

Procedure:
Cesium carbonate (1.75 g, 5.4 mmol) was added to a solution of 4-nitro-1,3-dihydro-2H-benzimidazol-2-one (800 mg, 4.5 mmol, described in Intermediate 26) and tert-butyl bromoacetate (0.791 mL, 5.4 mmol) in DM (15 mL). After 18 h, the reaction was quenched with H2O (100 mL) and the solid precipitate was collected by filtration. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—95:5, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]=12
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1nsc2nc(C)cc(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
A mixture of pyridinothiazolone 4 (500 mg, 2.77 mmol), methyl 2-bromoacetate (900 mg, 5.88 mmol), Cs2CO3 (700 mg, 3.07 mmol) and DIEA (1.5 mL, 8.61 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room temperature for 5 h, and then concentrated under reduced pressure. In addition to the main N-alkylation product 7 (55%), the title compound (50 mg, 7% yield) was obtained after purification by flash chromatography on a silica gel column (EtOAc/hexane (1:4)). C11H12N2O3S; white solid; mp 89-91° C.; IR vmax (neat) 3053, 2958, 2929, 2851, 1767, 1592, 1562, 1504, 1445, 1398, 1334, 1228, 1128, 1039, 961 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.91 (1H, s), 5.05 (2H, s), 3.78 (3H, s), 2.89 (3H, s), 2.61 (3H, s); 13C NMR (100 MHz, CDCl3) δ 172.3, 168.4, 160.7, 160.2, 145.6, 121.4, 115.7, 64.2, 52.3, 24.6, 19.1; ESI-HRMS calcd for C11H13N2O3S: 253.0647. found: m/z 253.0647 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH2:9].CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N:17]=1>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH:9][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N:17]=1
Reactant: COc1ccccc1CSCCN
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Solvent: O
Product: COc1ccccc1CSCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
2-(2-Methoxybenzylthio)ethylamine (1.18 g) and 2-methylthio-5-(3-pyridylmethyl)-4-pyrimidone (1.0 g) were fused together at 170° for 50 minutes and allowed to cool. Water was added and the mixture was extracted at pH 13 with chloroform (discarded), adjusted to pH 7 and extracted a second time with chloroform. The second extract was evaporated to give 2-[2-(2-methoxybenzylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone as an oil which was treated with hydrogen chloride in ethanol and recrystallised from ethanol-ether to give the dihydrochloride m.p. 180°-183°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Cl[C:10]1[C:14]2[CH:15]=[C:16]([CH:28]=[O:29])[C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)=[C:18]([F:19])[C:13]=2[O:12][N:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][C@H:22]1[O:23][C@@H:24]([CH3:26])[CH2:25][N:20]([C:17]2[C:16]([CH:28]=[O:29])=[CH:15][C:14]3[C:10]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)=[N:11][O:12][C:13]=3[C:18]=2[F:19])[CH2:21]1
Reactant: OB(O)c1cn[nH]c1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1CN(c2c(C=O)cc3c(-c4cn[nH]c4)noc3c2F)C[C@H](C)O1

Procedure:
1H-pyrazole-4-boronic acid pinacolate ester, 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos), and tris(dibenzylideneacetone)dipalladium(0) were reacted using a method similar to the one described for the synthesis of Intermediate 554.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(C)Cc1ccc(C(=O)Cc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A solution of the product from step (b) (11.1 g) in trifluoroacetic acid (16 ml) was stirred at room temperature and triethylsilane (12.5 ml) added. The mixture was stirred overnight at room temperature, followed by 3 hours at 50° C. during which further portions of triethylsilane (3 ml each) were added after 1.5 hours and 2.5 hours, then poured into water (250 ml). The latter was extracted with ether (x2) and the combined extracts washed with water (x2), dried over MgSO4, and evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (1:4 v/v). The eluate was evaporated under reduced pressure to give 11.0 g of the desired product.