Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]1[N:19]([CH3:38])[C:20](=[O:37])[C:21]([O:28]C(=O)C2C=CC=CC=2)=[C:22]([C:24]([O:26]C)=O)[N:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.CC#N.O>CO>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]1[N:19]([CH3:38])[C:20](=[O:37])[C:21]([OH:28])=[C:22]([C:24]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:26])[N:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Cn1c(C2Cc3ccccc3N2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 60 °C

Procedure:
The crude product of Step 2 was dissolved in MeOH and 4-fluorobenzylamine (3.5 eq.) added. The solution was stirred at 60° C. over night. The title product was obtained by preparative RP-HPLC (C18, gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and ethanesulfonyl chloride (45 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give ethanesulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 379.20.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]1([Li])C=CC=CC=1.O=C1C=CC=C[CH:33]1[S:38]([CH:40]1C=CC=C[C:41]1=[O:46])=[O:39]>C1COCC1>[CH3:24][O:46][CH:41]=[CH:40][S:38]([CH:33]=[CH:4][O:3][CH3:2])=[O:39]
Reactant: [Li]c1ccccc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=CC=CC1S(=O)C1C=CC=CC1=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=CS(=O)C=COC
Temperature: -78 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a suspension of methoxymethyl triphenylphosphonium chloride (1.42 g, 4.14 mmol) in dry THF (15 mL) at -78° C. was added dropwise a 1.77M phenyllithium solution (2.34 mL, 4.14 mmol), and the cooling bath was removed. Stirring was continued for 3 h to give a deep red solution. This solution was cooled to -78° C., and a solution of keto phenyl sulfoxide 110 in THF (10 mL) was added dropwise by cannula. The resulting mixture was then allowed to warm to rt over 5 h, stirred for an additional 5 h, and quenched with water (25 mL). The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to give the crude product. Purification by silica gel chromatography (1:1=hexane:ethyl acetate) afforded 0.644 g (89%) of the desired product 111 as a mixture of the four diasteromers. 1H NMR (400 MHz, CDCl3); δ 1.20-2.98 (m, 13H), 3.47, 3.49, 3.52, 3.53 (s, 3H), 5.69, 5.71, 5.80, and 5.81 (br s, 1H), 7.22-7.66 (m, 5H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)[NH2:13]>C(O)C.O>[CH3:25][NH:24][S:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:12][N:13]=[CH:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:16]=1)(=[O:23])=[O:22]
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Reactant: O=CCSc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(NN=CCSc2ccccc2)cc1
Reaction time: 14 h
Yield: 78.9 %

Procedure:
A solution of (phenylthio)acetaldehyde (6.05 g) in absolute ethanol (180 ml) was added over 10 min to a solution of 4-hydrazino-N-methylbenzenemethanesulphonamide hydrochloride (10 g) in water (180 ml) with cooling. After addition of the aldehyde was complete, the mixture was stirred at 5° for a period of 14 h. The precipitated solid was filtered off, washed with water (200 ml), hexane (200 ml) and dried in vacuo to give the title compound (10.95 g), m.p. 110°-112°. T.l.c. (B) Rf 0.5 (KMnO4)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9]Cl)[CH:4]=1.[CH3:11][O-:12].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:12][CH3:11])[CH:4]=1
Reactant: C[O-]
Reactant: ClCc1cc(Cl)ccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)ccn1
Temperature: 70 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 4-chloro-2-chloromethylpyridine hydrochloride (0.43 g), sodium methoxide (1.11 g) and methanol (15 ml) was stirred at room temperature for 10 hours and at 70° C. for 7 hours. The reaction mixture was concentrated, and the residue was combined with water and methylene chloride, and the organic phase was separated. After washing with saturated aqueous sodium bicarbonate followed by drying and concentrating, a title compound (0.28 g) was obtained as a tan oil.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14]([O:16][CH2:17][CH2:18][OH:19])[CH3:15]>>[C:11]([OH:13])(=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15]
Reactant: CCOCCO
Reactant: O=C(O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCOCCCCCCCC(=O)O
Yield: 8 %

Procedure:
NaH (2.4 g, 0.05 mol) was allowed to react with 2-ethoxyethanol (50 mL) during 30 min. 8-Bromooctanoic acid (4.8 g, 0.021 mol) was added, the solution heated at reflux for 24 h, cooled, and the solvent removed in vacuo. The residue was dissolved in ether, washed with water, the aqueous phase acidified (pH 1, HCl), and washed again with ether. The organic phase was dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (silica gel, 10%-25% Et2O/CH2Cl2), and distilled (Kugelrohr) to afford the title compound (0.4 g, 8%) as a yellow oil (bp 232° C./0.02 torr). IR: 1750 cm-1 : 1H NMR: 1.3 (t, 3H); 1.35 (bs, 6H); 1.6 (m, 4H); 3.5 (m, 8H). Anal. Calcd for C12H24O4 : C, 62.07; H, 10.41%. Found: C, 61.95; H, 10.46%.
Reaction SMILES: ClC1N=C2C(=CC=1)C=C1N2[C@H](C)CNC1=O.[C:17]([O:21][C:22]([N:24]1[CH2:36][C@@H:35]([CH3:37])[N:34]2[C:26](=[CH:27][C:28]3[C:33]2=[N:32][C:31]([Br:38])=[CH:30][CH:29]=3)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([BH3-])#N.[Na+]>>[C:17]([O:21][C:22]([N:24]1[CH2:36][C@@H:35]([CH3:37])[N:34]2[C@@H:26]([CH2:27][C:28]3[C:33]2=[N:32][C:31]([Br:38])=[CH:30][CH:29]=3)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Br)nc3n21
Agent: C[C@@H]1CNC(=O)c2cc3ccc(Cl)nc3n21
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]2Cc3ccc(Br)nc3N21

Procedure:
This compound was prepared in analogy to Example 2, intermediate b) from (R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyano borohydride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C@@H:8]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:10]([CH2:11][CH2:12][C:13]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C:14]=3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:24])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:9]1>O1CCCC1>[OH:7][C@@H:8]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:10]([CH2:11][CH2:12][C:13]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C:14]=3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:24])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CCC2=C3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@@]21C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CCC2=C3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@@]21C
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A mixture of lithium aluminum hydride (6.7 g) in tetrahydrofuran (50 ml) is cooled to 0° C. and a solution of 3α, 12α-dihydroxy-5β-chol-8(14)-en-24-oic acid (15.3 g) in tetrahydrofuran (350 ml) is added to dropwise. The mixture is warmed to room temperature, stirred for about 17 hours, and quenched by dropwise addition of water (6.7 ml), 15% sodium hydroxide solution (6.7 ml), and water (6.7 ml). The mixture is filtered, washing the alumina salts with 20% ethanol in ethyl acetate, and the filtrate concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.1 %

Procedure:
To a stirred mixture of N-acetyl-4-hydroxypiperidine (7.1 g, 0.050 mol), 4-nitrophenol (7.1 g, 0.050 mol), PPh3 (16.3 g, 0.062 mol), and THF (50 mL) was added a solution of diethyl azodicarboxylate (10.8 g, 0.062 mol) in THF (16 mL). The mixture was stirred at room temperature for 48 hours, and then concentrated. The crude mixture was purified by flash chromatography (1% MeOH/EtOAc) to give 4.5 g (30%) of N-acetyl-4-(4-nitrophenoxy)piperidine as a yellow oil: 1H NMR (DMSO-d6): δ 8.10 (d, 2H) 7.05 (d, 2H), 4.80 (m, 1H) 3.80 (m, 1H), 3.65 (m, 1H), 3.15 (m, 1H), 3.00 (m, 1H), 2.00 (s, 3H), 1.90 (m, 2H), 1.65 (m, 1H), 1.50 (m, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[C:16]2[C:17]3([CH2:29][O:28]3)[C:18]3[C:23]([C:24]4([CH2:26][O:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[C:22]([Cl:27])[CH:21]=[CH:20][CH:19]=3>C1(C)C=CC=CC=1>[Cl:10][C:11]1[C:16]2[CH:17]([CH:29]=[O:28])[C:18]3[C:23](=[C:22]([Cl:27])[CH:21]=[CH:20][CH:19]=3)[CH:24]([CH:26]=[O:25])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc2c1C1(CO1)c1cccc(Cl)c1C21CO1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=CC1c2cccc(Cl)c2C(C=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.1 ml. of boron fluoride etherate in 100 ml. of anhydrous toluene is added 500 mg. of 1',5'-dichloro-dispiro[oxirane-2,9'(10'H)-anthracene-10',2"oxirane]. The mixture is stirred at room temperature for 6 hours and filtered. The filtrate is washed twice with 10 ml. portions of a mixture of 10 ml. of saturated sodium bicarbonate and 10 ml. of ice water, dried over anhydrous sodium sulfate and filtered. The toluene is removed by water pump evacuation at 30° C. to give 0.5 g. of the desired product as a pale yellow solid, mp. 160°-172° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]2[CH2:25][C:26]([O:28]C)=[O:27])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]2[CH2:25][C:26]([OH:28])=[O:27])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 48 h

Procedure:
Lithium hydroxide (0.041 g, 10.95 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)acetate (2.7 g, 7.3 mmol) in THF (45 ml) and water (45 ml), and stirring was carried out for 48 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was extracted with ethyl acetate and then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:17])([CH3:16])[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:17])([CH3:16])[C:12]([NH:14][NH:15][C:26](=[S:27])[NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(C)(C)C(=O)NN)cc1OC
Solvent: CCO
Product: COc1ccc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)cc1OC
Yield: 71.9 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-2-methylpropanehydrazide (1.04 g, 4.37 mmol) and 4-fluorophenyl isothiocyanate (1.34 g, 8.73 mmol) in EtOH (30 mL) was heated at reflux 2 h. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was triturated with Et2O. The solids were collected by filtration and dried in vacuo to give 2-(2-(3,4-dimethoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)hydrazinecarbothioamide (1.23 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (br s, 1H), 9.65 (br s, 1H), 7.38 (b, 1H), 7.17 (t, 3H), 6.94-6.82 (m, 4H), 3.73 (s, 3H), 3.71 (s, 3H), 1.52 (s, 6H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[C:37]([S:40]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)Cl)c1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
The 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol hydrochloride (306 mg, 0.84 mmol, Example 91, Step 1) was dissolved in CH2Cl2 (20 mL) and the solution was chilled to 0° C. To this solution was added triethylamine (292 μL, 2.10 mmol) followed by 4-nitrothiophene-2-sulfonyl chloride (210 mg, 0.923 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. Afterwards, the mixture was filtered and concentrated, the filtrate was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (86 mg).
Reaction SMILES: [C:1]([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)([OH:3])=[O:2]>[OH-].[Na+].O.[Pd]>[C:1]([CH2:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)([OH:3])=[O:2]
Reactant: O=C(O)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 87.8 %

Procedure:
A solution of 19.95 g of 10-(carboxymethyl-ene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 720 ml of 1N sodium hydroxide and 200 ml of water is hydrogenated at 1.7 bar and at a temperature in the region of 23° C. for 22 hours in the presence of 2 g of 10% palladium-on-charcoal. The reaction mixture is filtered and the filtrate is acidified with 95 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water (200 ml), then with acetone (5×200 ml) and dried at 80° C. under vacuum (1 mmHg; 0.13 kPa). 17.65 g of 10-(carboxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a light-grey solid, which product is converted into the sodium salt of formula C15H10N3O3Na (Analysis, % calculated C: 59.41, H: 3.32, N: 13.86, O: 15.83, Na: 7.58, % found C: 59.3, H: 2.9, N: 13.7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:19][C:18](=[O:20])[C@@H:13]([C:14]([CH3:16])([CH3:17])[CH3:15])[NH:12][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
N-(3 Methoxyphenylsulfonyl)D-tert-leucine (3.03 g, 10.1 mmol) is dissolved in DMF (30 ml). Potassium Carbonate (2.81 g, 20.1 mmol) is added followed by Benzyl Bromide (1.21 ml, 9.95 mmol) and the reaction is stirred at ambient temperature for 18 hours. The reaction mixture is partitioned between Ethyl Acetate and 1 N HCl. The organics are separated and washed with brine, dried over MgSO4 and concentrated. The residue is purified by column chromatography eluting with a gradient of 5-60% (Hex-EtOAc) to give the title compound (3.08 g, 78% yield). Mass spectrum (392.2; M+1, 390.2; M−1).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C[Li].C1C[O:17][CH2:16]C1>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:16][O:17]1
Reactant: C#CCCOC1CCCCO1
Reactant: C1CCOC1
Agent: [Li]C
Product: C1CCC(OC2CCCCO2)OC1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
2-(3-Butynyloxy)tetrahydro-2H-pyran (112.5 g, 0.729 mole) was added dropwise to a solution of methyllithium (500 mL of MeLi 1AM in ether, 0.7 mole) in 1 L of anhydrous THF at -30° C. under argon atmosphere in a 5 L round bottom flask. After this addition was completed, the cooling bath was removed and the solution was allowed to stand at room temperature for 4 hours. The solution was cooled again at -30° C. and a solution of ketone 3 (75 g, 0.2 mole) in 2.5 L of anhydrous TTh was added dropwise. After completing this addition, the cooling bath was removed and the mixture was allowed to stand at room temperature for 16 h. To this mixture, 100 mL of brine were added and the solution was diluted with ethyl acetate, washed with brine and dried with anhydrous MgSO4. The solvent was then evaporated and crystallization took place after a short period of time. Hexane was added to complete the precipitation. The solid was then filtered and washed with hexane. The compound 4 was used in the next step without further purification. Yield: 95.8 g (90%). 1H NMR δ (CDCl3, 300 MHz, TMS): 0.82 (s, 3H, 18CH3), 1.01 (s, 3H, 19CH3), 2.52 (t, 2H, J=6.8 Hz, CCCH2), 3.15-3.44 (m, 4H, SCH2), 3.50-3.56 (m, 2H, CH2OTHP), 3.75-3.90 (m, 2H, pyran OCH2), 4.66 (s, 1H, OCHO), 5.47 (s, 1H, C-4H.
Reaction SMILES: [NH3:1].C(O[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[N:15]4[C:19]([C:20](=[O:21])[C:8]([C:9]=23)=[CH:7][N:6]=1)=[CH:18][CH:17]=[C:16]4[N+:22]([O-:24])=[O:23])C.O>N1C=CC=CC=1>[NH2:1][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[N:15]4[C:19]([C:20](=[O:21])[C:8]([C:9]=23)=[CH:7][N:6]=1)=[CH:18][CH:17]=[C:16]4[N+:22]([O-:24])=[O:23]
Reactant: N
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A stream of ammonia is passed into a solution of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5 g) in pyridine (200 cc) until the solution is saturated. The solution obtained is then stirred at a temperature of about 20° C. for 16 hours. The resulting suspension of red crystals is poured into iced water (600 cc). The crystalline precipitate is filtered off and then washed successively with water (5 × 10 cc), ethanol (3 × 10 cc) and then diethyl ether (2 × 20 cc). After drying under reduced pressure (1 mm Hg) at 25° C., 4-amino-10-nitro-7-oxo-7H-indolizino[7,6,5-de]-isoquinoline (4.18 g) is obtained in the form of orange-red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[IH:11].CS[C:14]1[NH:15][CH2:16][CH2:17][N:18]=1>CO>[IH:11].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14]1[NH:18][CH2:17][CH2:16][N:15]=1
Reactant: CSC1=NCCN1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: I
Solvent: CO
Product: Clc1ccc(CNC2=NCCN2)cc1Cl
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (0.352 g, 2.0 mmol) in methanol (5 ml) was added 2-methylthio-2-imidazoline hydroiodide (0.488 g, 2.0 mmol) and the mixture was heated to reflux for 4 h. The solvent was partly removed by evaporation (to approx. 1 ml) and ether (5 ml) was added. After stirring for 15 min the precipitating white solid was removed by filtration and washed with ether. It was obtained 130 mg (18%) of a white solid; MS (ISP): 244.1; 246.0 ([M+H]+.).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([N+:13]([O-])=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(O)(=O)C.[Zn]>[Br:16][C:11]1[CH:12]=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH2:13])=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1ncccc1OC1CCCC1
Reactant: BrBr
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
3-(cyclopentyloxy)-2-nitropyridine (8.2 g, 39.3 mmol) in acetic acid (90 mL) was cooled in a water bath. Zn dust (10 microns) (12.9 g, 197 mmol) was slowly added in portions over 15 minutes and the reaction stirred for an additional 30 minutes. The solution was filtered over celite and the solids were rinsed with DCM. The filtrate was concentrated to about 90 mL of acetic acid. To this solution was added bromine (2.0 mL, 39.3 mmol) in dropwise manner. After 15 minutes, the material was concentrated and neutralized with saturated NaHCO3 solution. The material was extracted with dichloromethane and the organic layer was dried, and concentrated. Flash chromatography gave 5-bromo-3-(cyclopentyloxy)pyridin-2-amine (5.26 g, 52% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]2)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:25]O>>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][C@H:14]([CH3:19])[O:15][C@H:16]([CH3:18])[CH2:17]2)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH3:25])=[O:6]
Reactant: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1

Procedure:
To a stirred solution of 3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoic acid (Intermediate 35, 10.0 g, 34.8 mmol) in methanol (50 mL) was added concentrated H2SO4 (1 mL) and the solution was refluxed for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL). The organic layer washed with H2O (2×20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography with ethyl acetate-pet. ether to give product as a solid. Yield: 9.0 g (86%)