Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C(SCl)[C:5]([C:8](Cl)=[O:9])=C[CH:7]=1.C([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)(C)C>>[C:8]([NH:23][CH2:22][CH:19]1[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]1)(=[O:9])[CH3:5].[CH:2]([Cl:1])([CH3:3])[CH3:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1SCl
Reactant: CC(C)N1CCC(CN)CC1
Product: CC(=O)NCC1CCNCC1
Product: CC(C)Cl

Procedure:
2-(1-sopropylpiperid-4-ylmethyl)-6-chloro-1,2-benzisothiazolin-3-one is obtained analogously to Example 33 by reacting 3-chloro-6-chlorocarbonylphenylsulfenyl chloride and 1-isopropyl-4-aminomethylpiperidine [boiling point 15 :95°-97° C.; obtained from 4-acetylaminomethylpiperidine and isopropyl chloride analogously to Singh et al., J. Med. Chem. 12, 949 (1969) and Werbel et al., supra]. After recrystallization in acetone, yellow crystals of melting point 134°-135° C. are obtained; yield: 37% of theory.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1C#CCO
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Methyl 2-iodobenzoate (25 g, 95 mmol), prop-2-yn-1-ol (8.02 g, 143 mmol) and TEA (26.6 ml, 191 mmol) were added to a deareated mixture of Pd(PPh3)4 (0.220 g, 0.191 mmol), copper(I) iodide (0.073 g, 0.382 mmol) in DMF (60 ml). The resulting mixture was stirred at 90° C. for 5 hrs and then at 40° C. overnight. The reaction mixture was poured into EtOAc (600 ml) and washed with brine (600 ml). Organic phase was then concentrated and the dark oil was rinsed with Et2O (600 ml). The mixture was filtered, and then concentrated to give the title compound as deeply brown oil (13.0 g). This compound was used in the next step without any further purification and characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([NH2:28])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH:34]=1.C1N=C[N:49]([C:52]([N:54]2C=NC=C2)=[O:53])C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:27]([NH:28][C:52]([NH:46][C:43]4[CH:44]=[CH:45][C:40]([O:39][C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)=[CH:41][CH:42]=4)=[O:53])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2].[NH2:49][C:52]([NH2:54])=[O:53]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2cccnc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3ccc(Oc4cccnc4)cc3)cc2)CC1
Product: NC(N)=O

Procedure:
4-{2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester was coupled with 4-(pyridin-3-yloxy)phenylamine by reaction with CDI in a similar manner to that described above, to provide the urea 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (LC-MS [M+H]+=655, RT=3.51 min). Step 2. To a solution of 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature for 16 h, concentrated at reduced pressure, re-dissolved in methanol and purified by preparative HPLC. The HPLC fraction containing the desired product was basified by addition of saturated aq Na2CO3 and then extracted with EtOAc. Evaporation of the solvent at reduced pressure gave the desired product 1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea (46.6 mg, 26%). 1H-NMR (DMSO-d6) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35 (m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=555.3, RT=2.73 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C#N)cc1Br
Temperature: 25 °C

Procedure:
Mix 3-bromo-4-hydroxy-benzonitrile (1.520 g, 8.0 mmol), allyl bromide (1.161g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) and potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). Heat the mixture to reflux for 12 h. Cool to ambient temperature, add EtOAc, wash the organic layer with water, and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to obtain the desired intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[CH3:24]>C1(C)C=CC=CC=1>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)[CH:5]=2)=[O:27])[CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(C)c(Cl)c2)cc1N1CCN(C)CC1
Product: Cl

Procedure:
A mixture of 13.6 mmol (3 g) of 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine and 13.6 mmol (2.26 g) of 3-chloro-4-methylphenyl isocyanate in 100 ml of toluene is heated at reflux for 2 hours. After cooling, the precipitate obtained is filtered off, and rinsed twice with diethyl ether. The solid obtained is purified by chromatography on silica gel, using as eluant a 96/4/0.4 dichloromethane/methanol/ammonium hydroxide mixture, to yield the expected product. The corresponding hydrochloride is obtained by the action of an ethanolic HCl solution.
Reaction SMILES: [Cl:1][Pd:2][Cl:3].[C:4]12[CH2:10][C:7]([CH2:8][CH2:9]1)=[CH:6][CH:5]=2.[CH3:11][O-:12].[Na+]>CO>[Pd:2]([Cl:3])[Cl:1].[CH3:11][O:12][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2
Reactant: C[O-]
Reactant: C1=C2CCC(=C1)C2
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CO
Product: COC12C=CC(CC1)C2

Procedure:
The above-prepared norbornadiene dichloropalladium (1.40 g) was added to 20 mL of methanol in a flask made of glass where inner air was substituted with highly pure argon and then the inner temperature was made −40° C. using a dry ice bath. Into this was dropped 1.5 mL of a 28% methanolic solution of sodium methoxide (manufactured by Wako Pure Chemical Industry). The mixture was made to react for 1 hour and returned to room temperature. The resulting yellow solid was sucked and washed with methanol to give 1.22 g of methoxynorbornene palladium chloride dimer.
Reaction SMILES: [Cl:1][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1.S(Cl)(Cl)(=O)=O>CCCCCCC>[Cl:1][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([S:7][S:7][CH:4]2[CH2:5][CH2:6][Si:2]([Cl:1])([CH3:8])[CH2:3]2)[CH2:3]1
Reactant: C[Si]1(Cl)CCC(S)C1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCCCCCC
Product: C[Si]1(Cl)CCC(SSC2CC[Si](C)(Cl)C2)C1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a 0.5 liter 3-neck round bottom glass flask fitted with a magnetic stirrer, dropping funnel and a nitrogen source was added 33.4 grams (0.20 moles) of 1-chloro-1-methyl-3-mercaptosilacyclopentane and 0.025 liters of n-heptane. Sulfuryl chloride, 13.5 grams (0.10 moles) was rapidly added at 25 C. to the stirred mixture within 3 minutes. After an additional stirring for 42 hours at ambient room temperature, the solvent was removed at about 50 -75 C./20-50 mm and nitrogen bubbled through the viscous residue for 16-20 hours. GLC analysis of the residue (27 grams) indicated 90.2 wt.% of the desired disulfide and 9.8 wt.% of the mercaptan starting material. Based on the purity of the residue, a 74 mole % yield was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH:15]=O)[CH:12]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:53]CCCl>C(OCC)C>[ClH:53].[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH2:15][N:29]2[CH2:30][C@H:31]3[C@:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=4)([CH2:32]3)[CH2:28]2)[CH:12]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: ClCCCl
Reactant: Cc1ccsc1-c1cn(CCC=O)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccsc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 3-[5-(3-methyl-thiophen-2-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep29, 16 mg, 0.04 mmol) in DCE (3 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 20 mg, 0.05 mmol) in DCE (1 mL), AcOH (6 μl, 0.05 mmol) and NaBH(AcO)3 (30 mg, 0.08 mmol) were added and the mixture was stirred at room temperature overnight. Diethylether was then added and the mixture was washed with 1N solution of HCl, then with aqueous saturated NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the title compound (8 mg, 42% yield) as a free base.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH2:21]>O1CCCC1>[I:20][C:18]1[CH:17]=[CH:16][C:15]2[NH:21][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: Nc1ccc(I)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
1,1′-Carbonyldiimidazole (13.6 g) was added to a solution of 2-amino-4-iodophenylamine (13.2 g) [see Makromol. Chem. (1993), 194(3), 859-8681] in tetrahydrofuran (100 ml). The reaction mixture was stirred for 18 hours at room temperature, after which time the solvent was removed under reduced pressure, and the residue partitioned between 1N aqueous sodium hydroxide and diethyl ether. The aqueous was acidified with concentrated aqueous hydrochloric acid, and the resulting white precipitate filtered off and washed with water to afford 5-iodo-1,3-dihydro-2H-1,3-benzimidazol-2-one (14.0 g) as a white solid.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4].CS(C)=O>O>[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:2])=[O:23])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4]
Reactant: [NH4+]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(NC(N)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 85 °C
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, ammonium hydroxide (2 mL) was slowly added to 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13B) (66 mg, 0.13 mmol). Dimethylsulfoxide (1 mL) was slowly added. The reaction was then heated to 85° C. for 24 hrs. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.2) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13C) (20 mg, 35%, light yellow powder).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[F:12][C:4]1[CH:3]=[C:2]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)cc1F

Procedure:
A mixture of EXAMPLE 50A (4 g), 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (5.44 g), and dichlorobis(triphenylphosphine)palladium(II) (1.2 g) in 7:3:2 DME/water/ethanol (300 mL) and 2M aqueous Na2CO3 (17.2 mL) at 80° C. was stirred for 140 minutes, cooled and concentrated. The concentrate was dissolved in ethyl acetate, washed with brine and concentrated. The concentrate was flash chromatographed on silica gel with 1:4 ethyl acetate/hexane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:21][N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1nccc2cc(OC3CCNCC3)ccc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCC(Oc2ccc3c(N)nccc3c2)CC1
Reaction time: 72 h
Yield: 52.7 %

Procedure:
Three drops of glacial acetic acid was added to a solution of 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (35 mg, 0.14 mmol) in N, N-dimethylformamide (1 ml), followed by addition of formaldehyde (37% aqueous solution, 200 mL). Sodium triacetoxyboro-hydride (150 mg) was added to the mixture, which was shaken for 72 h. Saturated aqueous sodium hydrogen carbonate was added and then the mixture acidified with acetic acid. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 6-(1-methylpiperidin-4-yloxy)-isoquinolin-1-ylamine (19 mg), EIMS: m/z=258.5 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[O:22]=[C:23]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:24](OCC)=[O:25]>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[N:12]([C:8]3[CH:9]=[C:10]([CH3:11])[C:5]4[N:6]([C:2]([CH3:1])=[N:3][N:4]=4)[CH:7]=3)[C:24](=[O:25])[C:23](=[O:22])[CH:29]2[C:30](=[O:33])[CH2:31][CH3:32])=[CH:16][CH:15]=1
Reactant: Cc1cc(N)cn2c(C)nnc12
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: O=Cc1ccc(Cl)cc1
Product: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 60.1 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate at 110° C. for 4 hr. tR: 0.79 min (LC-MS 2); ESI-MS: 411 [M+H]+, ESI-MS: 409 [M−H]− (LC-MS 2).
Reaction SMILES: [C:1](#N)C.[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:16][CH3:17])[C:14]=1F)[N:11]([C@@H:18]1[CH2:20][C@@H:19]1[F:21])[CH:10]=[C:9]([C:22]([OH:24])=[O:23])[C:8]2=[O:25].Cl.Cl.[CH3:28][C@:29]1([NH2:36])[C:33]2([CH2:35][CH2:34]2)[CH2:32]N[CH2:30]1>C(N(CC)CC)C>[OH2:16].[OH2:16].[NH2:36][C@:29]1([CH3:28])[C:33]2([CH2:35][CH2:34]2)[CH2:32][CH:1]([C:14]2[C:13]([O:16][CH3:17])=[C:12]3[C:7]([C:8](=[O:25])[C:9]([C:22]([OH:24])=[O:23])=[CH:10][N:11]3[C@@H:18]3[CH2:20][C@@H:19]3[F:21])=[CH:6][C:5]=2[F:4])[CH2:30]1
Reactant: CC#N
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@@]1(N)CNCC12CC2
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1c(C2CC3(CC3)[C@@](C)(N)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Product: O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
An acetonitrile solution (24 mL) containing 6,7-difluoro-1,4-dihydro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), (7S)-7-methyl-5-azaspiro[2.4]heptan-7-amine dihydrochloride (3 g), triethylamine (1.34 mL), and boron trifluoride-tetrahydrofuran complex (2.68 g) was stirred at room temperature for 30 minutes. Boron trifluoride-tetrahydrofuran complex (0.27 g) was further added to the solution, followed by stirring for one hour at the same temperature. Triethylamine (5.37 mL) was further added to the reaction mixture, followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 2 hours, and the solvent was evaporated. 90% Hydrated methanol was added to the residue, and the pH of the product was adjusted to 8 by use of 5N aqueous sodium hydroxide. The thus-obtained mixture was stirred at 60° C. for 40 minutes, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 5° C. for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 4.23 g of the title compound (yield: 93%). Spectral data of this compound coincided with those obtained in Example 1.
Reaction SMILES: [CH:1]1[C:17]2[C:16]([C:18]([OH:20])=[O:19])=C3[C:7](=[C:8]4C(=N3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:23]I.[CH3:25][N:26]([CH:28]=O)[CH3:27]>>[CH3:27][N:26]1[C:25]2[C:16]([C:18]([O:20][CH3:23])=[O:19])=[C:17]3[C:5]([CH:4]=[CH:3][CH:2]=[CH:1]3)=[N:6][C:7]=2[C:8]2[C:28]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Product: COC(=O)c1c2ccccc2nc2c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
A mixture of quindoline-11-carboxylic acid (2.6 g, 10 mmol) from Example 1, DMF (25 mL), KOH (2.24 g, 40 mmol), BaO (6.27 g, 40 mmol) and methyl iodide (9.7 mL, 130 mmol) was stirred at room temperature for 48 hours, then partitioned between benzene (60 mL) and water (100 mL). The benzene layer was washed with water (2×60 mL), dried and concentrated. The residue was recrystallized from hexane to afford 1.14 g (39.3%) of the title compound as light yellow crystals, mp 127° C.; 1H NMR (CDCl3) δ 8.49 (d, J=8.0, 1H), 8.31(d, J=8.0, 1H), 7.95 (d, J=8.4, 1H), 7.68-7.55 (m, 3H), 7.42 (d,J=8.0, 1H), 7.37 (t, J=7.2, 1H), 4.14 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3) δ 167.98, 146.93, 145.64, 143.25, 130.27, 129.66, 126.52, 123.55, 122.92, 122.02, 121.28, 120.42, 115.77, 108.70, 52.71, 30.75; MS (EI, m/z) 290.1 (M+).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3](O)=[O:4].O.[NH2:15][NH2:16]>CO.S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3]([NH:15][NH2:16])=[O:4]
Reactant: COc1ccc(C(O)C(=O)O)cc1
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)C(=O)NN)cc1
Reaction time: 1 h

Procedure:
To a solution of hydroxy-(4-methoxy-phenyl)-acetic acid (45 g, 0.25 mol) in 300 ml of methanol are added 30 drops of concentrated sulfuric acid at room temperature and the resulting mixture is heated to reflux for 4 hours. Subsequently the mixture is cooled and evaporated in vacuo. The remainder is taken up in water and extracted with ethyl acetate. The combined organic layer isn washed with brine, dried over magnesium sulfate and evaporated. The residue, which is hydroxy-(4-methoxy-phenyl)-acetic acid methyl ester, is dissolved in 350 ml of diethyl ether. Hydrazine monohydrate (47 ml, 0.95 mol) is added dropwise at room temperature and the mixture is stirred for 1 hour. The reaction mixture is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated, the remaining hydroxy-(4-methoxy-phenyl)-acetic acid hydrazide is sufficiently pure to be used directly in the next step.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[CH2:37][O:36][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20]O)[O:17][C:16]2=[O:22])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][N:35]=[N+:36]=[N-:37])[O:17][C:16]2=[O:22])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(N2CCSCC2)c(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(c2cc(F)c(N3CCSCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(5R)-3-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-oxazolidin-2-one (Intermediate 12) (15 g, 45.5 mmol) was dissolved in a mixture of triethylamine (9.6 ml, 68 mmol) and dichloromethane (200 ml). The resulting solution was cooled to 0° C. and methane sulfonyl chloride (4.6 ml, 59 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours then allowed to warm to room temperature. Water (200 ml) was added and then the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo. This intermediate was dissolved in dry DMF (120 ml). Sodium azide (11.8 g, 181 mmol) was added and the reaction mixture stirred at 70° C. overnight. It was diluted with dichloromethane (700 ml), washed with water (200 ml) and brine (200 ml) and dried over magnesium sulfate. Concentration in vacuo gave 16 g of the title compound.