Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH2:27])=[S:26])[CH2:20]2)=[O:18])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[S:26][CH:2]=[C:3](/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:27]=3)[CH2:20]2)=[O:18])=[CH:28][CH:29]=1
Reactant: NC(=S)NC1CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: CCOC(=O)/C=C/C(=O)CCl
Solvent: CC#N
Product: CCOC(=O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.5 g) and N-[1-(4-chlorobenzoyl)-3-pyrrolidinyl]thiourea (0.8 g) in acetonitrile (10 mL) was stirred at 70° C. for 3 hours, and the mixture was evaporated in vacuo. To the residue was added a solution of AcOEt and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using AcOEt as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate (1.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[NH:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(=O)([O-])[O-].[Na+].[Na+]>[C:18]([N:14]1[C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][S:11][CH:10]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:14]1[C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][S:11][CH:10]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:25]
Reactant: O=C(Cl)CCCCCC(=O)Cl
Reactant: O=C(O)C1CSC(c2cccc([N+](=O)[O-])c2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)[C@@H]1CSC(c2cccc([N+](=O)[O-])c2)N1C(=O)CCCCCC(=O)N1C(c2cccc([N+](=O)[O-])c2)SC[C@H]1C(=O)O
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a stirred solution of (4R)-2-(3-nitrophenyl-4-thiazolidinecarboxylic acid (5.1 g) in 1M sodium carbonate (40 ml), heptanedioyl dichloride (2.1 g) was added dropwise under ice-cooling. The reaction mixture was stirred for 1 hour at the same temperature, and the separated crystals were filtered to give 4.7 g (69%) of the titled compound as disodium salt: mp 111°-113° C. (dec.) (water); [α]D25 +88.2° (c=0.5, methanol). IR (nujol, cm-1): 1635 (CON), 1585 (COO-), 1520 and 1355 (NO2), 1095, 730. TLC: Rf value* 0.28.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:14][CH2:15]O)[C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][N:6]=1.C([N:19](CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[N:4]1([C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][N:6]=2)[CH2:14][CH2:15][NH:19][CH2:2][CH2:3]1
Reactant: OCCN(CCO)c1nsc2ccccc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
Crude 3-[bis(hydroxyethyl)]amino-1,2-benzisothiazole (6.0 mmol) was dissolved in 20 ml of acetonitrile and triethylamine (18 mmol). Methanesulfonyl chloride (13 mmol) was dropwise added at 0-4° C. The resulting mixture was stirred at this temperature for 1 hour and at room temperature for 3-5 hours. The reaction mixture was washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in methanol-ammonium hydroxide solution and heated to reflux. After 20-24 hours at reflux, the solution was sampled for thin-layer chromatography (elution with methylene chloride/isopropanol/triethylamine, 15:5:1) which showed that the reaction was complete. Half volume of methanol was evaporated under reduced pressure and water (30 mL) was added, following by toluene (50 ml). Then the separated aqueous layer was washed with fresh toluene (10 ml). The combined toluene layers were washed with water (20 ml) and then treated with decolorizing carbon. The mixture was heated to reflux and filtered hot through celite. The celite cake was rinsed with toluene (10 mL), and the combined washing and filtrate were concentrated at reduced pressure to 10 mL. Isopropanol (22 ml) was added to the concentrate and the yellowish solution was cooled to 20° C. The pH of the solution was slowly adjusted to 3.5-4.0 with of concentrated hydrochloric acid. The resulting slurry was cooled to 0-5° C., stirred for 1 hour, and then filtered. The product was washed with cold isopropanol and dried in vacuum at 40° C. for 24 hours. The title compound (4.32 mmol) was isolated as a light yellow solid in 71% yield (>98.5% purity).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: Nc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 44 %

Procedure:
To a 50 mL flask was added 10 (221 mg, 1 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 105 mg (44%) of 11 as a yellow solid:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:27][CH:26]1[CH3:38])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH:37][C:2]3[N:3]=[CH:4][C:5]4[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:6]=4[N:7]=3)=[CH:35][CH:36]=2)[CH2:27][CH:26]1[CH3:38])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Product: CC1CN(c2ccc(Nc3ncc4cc(C#N)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 66.1 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.424 mmol) gave 4-[6-(6-cyano-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (128 mg) [following SiO2 chromatography eluting with 1-2.5% MeOH/dichloromethane and subsequent trituration with diethyl ether]. The material is used directly in the next step.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:62])[F:61]>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:60]([F:61])([F:62])[F:63])[N:39]=2)[N:36]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3ccccc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as light yellow gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[S:5][C:6]=1[CH2:7][CH3:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]3[C@@H:63]([NH3+:64])[C:62]([F:66])([F:65])[CH2:61][CH2:60][CH2:59]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55](=[O:56])[NH:57][C@H:58]3[CH2:59][CH2:60][CH2:61][C:62]([F:66])([F:65])[C@@H:63]3[NH:64][C:9]([C:4]3[S:5][C:6]([CH2:7][CH3:8])=[C:2]([Br:1])[CH:3]=3)=[O:11])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: [NH3+][C@@H]1[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1(F)F
Reactant: CCc1sc(C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-5-ethylthiophene-2-carboxylic acid (300 mg, 1.15 mmol) and BOP (762 mg, 1.72 mmol) were dissolved in DMF (11.5 mL) and stirred at room temperature for 5 minutes. (1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride (432 mg, 1.16 mmol) was added followed by diisopropylethyl amine (0.50 mL, 2.87 mmol) and the solution was stirred at room temperature for 18 h. The solution was diluted with water, and extracted with dichloromethane (×3). The organic layers were collected, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H); 7.46 (dd, 2H); 7.36 (s, 1H); 7.35 (d, 2H); 7.23 (dd, 2H); 6.36 (d, 1H); 5.14 (d, 1H); 4.36 (dd, 1H); 4.29 (dd, 1H); 4.13 (dd, 1H); 4.01 (dd, 1H); 3.86 (dd, 1H); 2.70 (q, 2H); 2.82 (m, 1H); 2.17 (m, 1H); 1.86 (m, 2H); 1.65 (m, 1H); 1.43 (m, 1H); 1.18 (t, 3H). LRMS (APCI) calc'd for (C28H27BrF2N2O3S) [M+H]+, 589.1. found 589.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17](Cl)[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=[O:28])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:28])[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 120 °C
Reaction time: 22 h
Yield: 21 %

Procedure:
4-(2,8-Dichloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (1.0 g) was dissolved in dimethylsulfoxide (10 mL), and then sodium acetate (425 mg) and sodium bicarbonate (326 mg) were added to this solution. After stirring the reaction solution at 120° C. for 22 hours, 1 N aqueous hydrochloric acid (5.0 mL) and water (80 mL) were added to the reaction solution, and this was extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (200 mg).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].ClCCl.CO>C(O)C>[C:1]1([C@H:7]([CH2:12][CH2:11][OH:10])[C:8]([NH2:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC[C@H]1c1ccccc1
Reactant: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)[C@@H](CCO)c1ccccc1
Yield: 63.3 %

Procedure:
(S)-2-phenylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (S)-2-phenyl-4-hydroxybutyramide.
Reaction SMILES: O[C:2]1([CH3:20])[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH3:19].O.[NH2:22][NH2:23]>C(O)C>[CH3:19][O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=1[C:3]1[C:2]([CH3:20])=[N:23][NH:22][C:5](=[O:6])[CH:4]=1
Reactant: COc1ccc(C(F)(F)F)cc1C1=CC(=O)OC1(C)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1-c1cc(=O)[nH]nc1C
Temperature: 0 °C
Yield: 36.9 %

Procedure:
5-Hydroxy-4-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylfuran-2(5H)-one (Preparation 40, 3 g, 10 mmol) was dissolved in ethanol and cooled to 0° C. Hydrazine monohydrate (1.0 mL, 20 mmol) was added drop-wise to this solution, then the reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo, azeotoped with toluene and the crude material purified by silica gel column chromatography (ISCO™ Companion, 50% ethyl acetate in heptane elution) to afford the title compound as an off-white solid (1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:21])=[O:17])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCCCCCCNC
Reactant: O=C(Nc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Phenyl 4-fluoro-2-nitrophenylcarbamate (0.70 g) and N-methylheptylamine (0.33 g) were dissolved in xylene (5 ml) and the solution was heated under reflux for 2 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1-(4-fluoro-2-nitrophenyl)-3-heptyl-3-methylurea as an oily product.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=O)[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1.O.OC1C2N=NNC=2C=CC=1.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH3:43].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH2:40][CH2:41][O:42][CH3:43])[C:9](=[O:11])[CH2:8][CH:7]1[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Reactant: COCCNCCOCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCN(CCOC)C(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 8 h

Procedure:
To a solution of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid (3 g, 9 mmol) in dry DMF (25 ml) was added hydroxybenzotriazole hydrate (1.22 g, 9 mmol), N-methoxyethoxyethyl-N-methoxyethylamine (3.19 g, 18 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.59 g, 14 mmol), and the resulting reaction mixture was stirred overnight. Water (10 ml) was added, the mixture stirred an additional 2 hours and concentrated to dryness under reduced pressure. The residue was treated with 0.5N HCl and the pH adjusted to 6.5-6.9 by the additon of dilute NH4OH. The aqueous mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent, the residue was recrystallized from water to give N-methoxyethoxyethyl-N-methoxyethyl-(2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetamide, mp 156°-158° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:34]1[CH2:35][CH2:36][N:29]2[CH:30]([CH2:31][O:32][CH:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)[CH2:28]2)[CH2:33]1)(=[O:46])[CH3:45]
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (29 μL, 0.21 mmol), in DMF (1 mL) at 0° C., acetic anhydride (11 μL, 0.11 mmol) was added. The reaction was allowed to stir for 20 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 19 mg (35%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.10 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.14 (dd, 1 H), 4.33-4.21 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.68 (m, 1H), 3.39-3.27 (m, 2H), 3.06-3.00 (m, 1H), 2.76-2.64 (m, 2H), 2.41-2.37 (m, 1H), 223-2.11 (m, 1H), 2.07-1.95 (m, 1H), 1.99 (s, 3H); LC-MS [M+H]+=523, RT=2.24 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 95 °C
Yield: 99.5 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (0.0.442 g, 1.23 mmol) in DMF (10 mL) is added acetic anhydride (0.126 g, 1.23 mmol) and DMAP (0.08 g, 0.66 mmol). The mixture is heated at 95° C. for 1 h and then partitioned between water and ether after cooling. The organic layer is washed three times with water (60 mL), dried over magnesium sulfate and concentrated to give 0.49 g (99%) of N -{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:12]([OH:13])[C:11]([OH:17])=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Oc1nc2cc(Cl)c(Cl)cc2nc1O

Procedure:
4,5-dichloro-o-phenylenediamine and diethyl oxalate were reacted by the procedure of Cheeseman [J.C.S., (1962), p. 1174] to obtain 6,7-dichloroquinoxaline-2,3-diol which was reacted with phosphorus oxychloride/phosphorus pentachloride to form 2,3,6,7-tetrachloroquinoxaline.
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4](C(OCC)=O)[C:3]1=[O:21].O.[Li+].[Cl-]>CS(C)=O>[F:1][CH:2]1[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(F)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(=O)C(F)C1
Temperature: 125 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
The product from Step A was dissolved in DMSO (200 mL) and H2O (8.29 g, 460 mmol) followed by addition of LiCl (19.5 g, 460 mmol). The solution was warmed to 125° C. and the mixture was stirred overnight. The mixture was cooled to ambient temperature and partitioned between EtOAc (2.5 L) and water:brine (1:1, 2.0 L). The mixture was filtered through activated charcoal over Celite, which was washed with EtOAc, forming visible layers. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (10 to 80% EtOAc/hexanes) providing 4.5 g (21%) of the product as a thick pale orange oil.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:16]2=[O:27])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].CO>C1COCC1.C(Cl)(Cl)Cl>[CH:1]1([CH:9]([OH:10])[C:8]2[CH:11]=[CH:12][C:13]([N:15]3[CH2:19][CH2:18][N:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]=4[CH3:26])[C:16]3=[O:27])=[CH:14][C:7]=2[F:6])[CH2:3][CH2:2]1
Reactant: Cc1ccncc1N1CCN(c2ccc(C=O)c(F)c2)C1=O
Reactant: Br[Mg]C1CC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc(C(O)C3CC3)c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.41 %

Procedure:
A 0.5M solution of cyclopropyl magnesium bromide in THF (2.4 mL, 1.170 mmol) was added dropwise to 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (I-121a: 175 mg, 0.585 mmol) in dry THF (10 mL) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was quenched with aqueous NH4Cl solution and the THF layer was concentrated. The aqueous layer was extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (3% MeOH in CHCl3), followed by hexane wash, afforded 200 mg of the product (99.41% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CCCO)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1OC
Reaction time: 15 h
Yield: 82.2 %

Procedure:
Compound 18-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (2.97 g) and N-bromosuccinimide (1.99 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-3:1) to give the object product (2.17 g) as a pale-brown oil.