Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[C:5]([Cl:15])=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([C@H:44]([NH2:47])[CH2:45][OH:46])[CH:38]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:43][C:41]1[CH:40]=[C:39]([CH:44]([NH:47][C:12]([CH:10]2[CH2:9][N:8]([C:6]3[C:5]([Cl:15])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:11]2)=[O:14])[CH2:45][OH:46])[CH:38]=[CH:37][CH:42]=1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Reactant: O=C(O)C1CN(c2nc(Cl)ncc2Cl)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(CO)c1cccc(Cl)c1)C1CN(c2nc(Cl)ncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
1-(2,5-Dichloropyrimidin-4-yl)-azetidine-3-carboxylic acid (66 mg, 0.27 mmol, 1 equivalent) was dissolved in DMF (1 mL) together with EDCI (103 mg, 0.53 mmol, 2 equivalents), HOBt (18 mg, 0.13 mmol, 0.5 equivalent) and (S)-(+)-3-chlorophenylglycinol (67.4 mg, 0.32 mmol, 1.2 equivalents). Triethylamine (121 mg, 0.32 mmol, 1.2 equivalents) was then added and the resulting mixture was stirred at room temperature for 1 hour then warmed to 90° C. for 10 minutes. The crude reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction dried over sodium sulfate. The resulting crude oil was purified by HPLC Gilson (acetonitrile/water/0.1% TFA), yielding the title compound as a white solid (44 mg, 41%). HPLC Rt=5.528 minutes.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3F)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:1][C@@H:2]([CH3:5])[CH2:3][O:4][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[C:22]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:7]([Cl:6])[CH:8]=1)=[N:23][CH:24]=[N:25]2
Reactant: C[C@H](N)CO
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 51 %

Procedure:
The procedure described in Example 2.4 (preparation of starting materials) was repeated using (2S)-2-aminopropan-1-ol and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give 5-{[(2S)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine in 51% yield; Mass spectrum MH+ 436.4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Cu][C:17]#[N:18].Cl>CN1CCCC1=O>[CH3:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH:7]=1)[C:17]#[N:18]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of 1-bromo-5-methyl-2-nitro-4-trifluoromethyl-benzene from step 2 (49.80 g, 175 mmol) and copper(I) cyanide (16.5 g, 184 mmol) in 1-methyl-2-pyrrolidone (NMP) (180 mL) was heated up to 150° C. and stirred for 30 min under nitrogen atmosphere. The mixture was cooled to 23° C. and poured into 1 N HCl, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with heptane/ethyl acetate 4:1→2:1 to give the title compound as a light yellow solid (35.48 g, 88%). MS (EI) 230.1 [M].
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C:26]([Cl:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.[OH-].[Na+]>[ClH:28].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=1)[CH2:11]3
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccc(C)cc3)CCN1CC2
Product: Cl
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a cold mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (9 g, 0.034 mole) in 300 ml of toluene and 75 ml of 20% NaOH was added dropwise p-toluoyl chloride (6 g, 0.035 mole). The mixture was stirred in the cold for 1 hour and allowed to come to room temperature. The solid was collected by filtration and the toluene layer concentrated in vacuo whereupon the solid and concentrate were combined and chromatographed over silica gel using ethyl acetate-methanol (4:1) as eluant. The major fraction (6.2 g) was converted to the HCl salt with hydrogen chloride in a mixture of 2-propanol, methanol and ethyl acetate, isolated and twice recrystallized from methanol-ethyl acetate to yield 3.2 g of the desired product, m.p. (decomposed at 268°-70°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR21##
Reaction SMILES: [O:1]=O.[F:3][C:4]1([C:7]2[CH:12]=[CH:11]C(C)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.[CH:14](=[O:16])[CH3:15]>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[F:3][C:4]1([C:7]2[CH:12]=[CH:11][C:15]([C:14]([OH:1])=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: CC=O
Reactant: O=O
Reactant: Cc1ccc(C2(F)CC2)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C2(F)CC2)cc1
Yield: 46 %

Procedure:
Oxygen was slowly bubbled at 100° C. through a solution of 1-(1-fluoro-cyclopropyl)-4-methyl-benzene (470 mg, 3.13 mmol), cobalt(II)acetate tetrahydrate (117 mg, 0.46 mmol), and acetaldehyde (0.18 mL, 3.1 mmol) in acetic acid (30 mL) over 16 h. After cooling, the reaction mixture was evaporated and the residue triturated in water. The precipitate was collected by filtration to produce the title compound (257 mg, 46%). Light green solid, MS (EI) 180.1 (M+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc2cccc(C)c2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2cccc(C)c2c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
5.5 g of 1'-hydroxy-8'-methyl-2'-acetonaphthone was dissolved in 50 ml of N,N-dimethylformamide, to which 1.7 g of 60% sodium hydride was added, followed by agitation at 50° C. for 10 minutes. The reaction solution was returned to room temperature, in which 5.5 ml of benzyl chloride was dropped, followed by heating again to 70° C. for reaction for 1 hour. After returning to room temperature, water was added to the solution, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant reside was purified by silica gel column chromatography (15% ethyl acetate/hexane) to obtain 4.8 g of the captioned compound as a brown oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2(CC=O)[CH2:12][N:13](C(OC(C)(C)C)=O)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.NC1C=CC=CC=1.CCN(S(F)(F)F)CC.[C:40](O)([C:42]([F:45])(F)[F:43])=O>C(Cl)Cl>[F:43][CH:42]([F:45])[CH2:40][C:10]12[CH2:12][NH:13][C:8]3[C:9]1=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][C:2](=[O:1])[CH2:11]2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2(CC=O)CC(=O)Nc3cccc1c32
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: O=C1CC2(CC(F)F)CNc3cccc(c32)N1
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-oxo-2a-(2-oxoethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate, enantiomer A, (150 mg, 0.474 mmol, described in Intermediate 24) in CH2Cl2 (2 mL) at 0° C. was added DAST (0.125 mL, 0.948 mmol) and the mixture was stirred for 1 h. Additional DAST (0.066 mL) was added and the mixture was stirred for 1 h. To the resulting mixture was added TFA (2 mL) and stirring was continued for 1 h. The mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL). The layers were separated and the aqueous layer further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=239 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1.[OH-].[Na+]>O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: NNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 1,681 g of ethyl 4-chloro-quinoline-3-carboxylate, 1,017 g of p-chlorophenylhydrazine and 25 L of xylene is heated to 105° for 24 hours while stirring under nitrogen. The resulting suspension is cooled to 20°, combined with 14 L of 2 N aqueous sodium hydroxide, stirred for 15 minutes and diluted with 30 L of water. Stirring is continued for 1 hour, the aqueous phase separated, washed five times with 8 L of diethyl ether each, filtered and the filtrate treated with the solution of 1,600 g of ammonium chloride in 8 L of water while stirring under nitrogen. The resulting suspension is stirred overnight at room temperature, filtered and the residue washed 5 times with 12 L of hot water. This residue is dried at 5 mmHg and 90° and 1,665 g thereof are dissolved in 8.4 L of dimethylformamide at 130°. The solution is filtered and allowed to cool to room temperature while stirring. The resulting suspension is filtered, washed twice with 500 ml of cold dimethylformamide each, four times with 1 L of diethyl ether and the residue is dried at 0.1 mmHg and 100°, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one of the formula ##STR9## melting at 324°-327° with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:9][N:10]([CH2:11][CH2:12]2)[CH2:22][CH2:21][O:20]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Brc1ccc(C23CCN(CCO2)C3)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To an ambient solution of Example 54D (0.100 g, 0.186 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 ml). The reaction was stirred for 0.5 h, and the solution was then carefully added to a slurry of K2CO3 (3.0 g, 21.7 mmol) in dichloromethane (10 mL). After the evolution of gas ceased, the mixture was heated to 40° C. for 1 h. The mixture was cooled to room temperature and was diluted with water (10 mL). The layers were separated, and the aqueous was extracted with additional dichloromethane (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title product, which was used in the subsequent step without further purification. MS (ESI) m/z 268 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]([CH3:23])([C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C(=O)C=Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)CCc1ccccc1)C(=O)CCc1ccccc1
Yield: 77.8 %

Procedure:
4,4-Dimethyl-1,7-diphenyl-1,6-heptadiene-3,5-dione (11b, 0.15 g, 0.5 mmol) and palladium on activated carbon (0.20 g, 10%) were combined in ethyl acetate (25 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 1 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give 0.12 g (80%) of a pale yellow oil; 1H NMR: δ 1.25 (s, 6H), 2.60 (t, 4H, J=7.4 Hz), 2.80 (t, 4H, J=7.0 Hz), 7.18 (m, 10H); 13C NMR: δ 21.1, 29.8, 40.2, 62.4, 126.1, 128.3, 140.7, 208.4; Exact mass calcd for C21H24O2: 308.1776, observed (M+H) 309.1843.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:27][CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29][CH2:30]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@H]1CC[C@H](Nc2nc(Cl)ncc2Cl)CC1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@H](NS(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
trans-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white solid (96 mg, 53%). m.p.=189-192° C.; LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.33 (d, 1H, J=7.5 Hz), 7.03 (d, 1H, J=8.0 Hz), 6.80 (s, 1H), 5.03 (d, 1H, J=7.2 Hz), 4.29 (d, 1H, J=7.5 Hz), 4.02-3.90 (m, 1H), 3.57 (t, 2H, J=5.5 Hz), 3.45-3.32 (m, 1H), 3.38 (s, 3H), 3.03 (s, 3H), 2.98-2.88 (m, 4H), 2.83-2.69 (m, 6H), 2.28-2.16 (m, 4H), 1.53-1.32 (m, 4H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]2[N:6]([CH:22]=[N:23][CH:24]=2)[C:7]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH:9]=1.C(N(CC)C(C)C)(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:34]([N:19]1[CH2:18][CH2:17][N:16]([C:7]2[N:6]3[CH:22]=[N:23][CH:24]=[C:5]3[C:4]([Br:3])=[CH:9][C:8]=2[C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH2:21][CH2:20]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc(Br)c2cncn2c1N1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Br)c2cncn2c1N1CCN(C(C)=O)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 8-bromo-N-methoxy-N-methyl-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-carboxamide dihydrochloride (500 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (0.69 mL, 4.0 mmol), followed by 4-dimethylaminopyridine (5 mg, 0.04 mmol). The reaction mixture was treated with acetic anhydride (0.13 mL, 1.4 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate, water (3×), and brine, dried over sodium sulfate, filtered and concentrated to give the desired product (0.41 g, 89%). This material was used without purification. LCMS for C16H21BrN5O3 (M+H)+: m/z=410.1, 412.1. Found: 409.8, 411.8.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:28]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][O:24][C:23](=[O:25])[C@H:12]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (S)—N-benzyloxycarbonyl-L-tryptophan 1a (2.45 g, 7.2 mmol) in 10 ml anhydrous CH2Cl2, was added DMAP (0.1 g, 0.82 mmol) and methanol (0.28 g, 11.8 mmol). At 0° C., DCC in CH2Cl2 solution was slowly added to the mixture and then it was allowed to warm to room temperature and stirred overnight. After twice filtration and evaporation, the residue was purified by flash column chromatography (n-hexane/EA, 4:1 to 2:1) and afforded the desired product (S)-2a as a colourless oil (2.5 g, 98%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.O>CN(C=O)C>[C:1]1([NH:7][C:8]([NH:15][CH2:14][CH2:13][CH2:12][Br:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCBr
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCBr)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
Phenyl isocyanate (1.4 ml, 13 mmol) was added to a solution of 3-bromopropylamine hydrobromide (2.5 g, 11 mmol) and triethylamine (1.7 ml, 12 mmol) in DMF (50 ml) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. After adding water, the mixture was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to afford N-phenylcarbamoyl-3-bromopropylamine (2.7 g, 96%); MS(FD) m/e 256 M+; 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 4H), 7.11 (m, 1H), 6.45 (br, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.41 (t, J=6.6 Hz, 2H), 2.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:10]2[C:9]3[CH:11]=[C:12]([S:19]([O-:22])(=[O:21])=[O:20])[CH:13]=[C:14]([S:15]([O-:18])(=[O:17])=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:23].Br[CH:26]([CH2:30][CH2:31]CC)[C:27]([OH:29])=[O:28].[C:34](OCC)(=O)[CH3:35]>>[C:27]([CH:26]([CH2:30][CH3:31])[CH2:34][CH2:35][O:17][S:15]([C:14]1[C:8]2[CH:7]=[CH:6][C:5]3[NH+:4]=[C:3]([CH3:23])[C:2]([CH3:24])([CH3:1])[C:10]=3[C:9]=2[CH:11]=[C:12]([S:19]([O-:22])(=[O:21])=[O:20])[CH:13]=1)(=[O:18])=[O:16])([OH:29])=[O:28]
Reactant: CCCCC(Br)C(=O)O
Reactant: CC1=Nc2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Reactant: CCOC(C)=O
Product: CCC(CCOS(=O)(=O)c1cc(S(=O)(=O)[O-])cc2c3c(ccc12)[NH+]=C(C)C3(C)C)C(=O)O
Temperature: 125 °C
Yield: 70 %

Procedure:
A suspension of 1,1,2-trimethylbenz[e]indol-6,8-disulfonate (4.82 g, 13.0 mmol), bromohexanoic acid (25 g, 130 mmol) in a 250 mL round bottom flask was heated in an oil bath at 125° C. for 40 h. After cooling to ambient temperature ethyl acetate (100 mL) was added the solid was triturated. Filtered to collect the solid, washed with ethyl acetate (3×50 mL), ether (2×20 mL) and dried. Further drying in an oven at 40° C. under high vacuum for 18 h gave 4.41 g (70.0%) of the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8]1>O>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH2:8][CH2:9]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 93.4 %

Procedure:
26.7 parts by weight of piperazine and 26.5 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 200 parts by volume of water are heated to 120° C. in an autoclave for 60 minutes and the mixture is then worked up as in Example 1. 30.9 parts by weight (93.4% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3quinolinecarboxylic acid are obtained.
Reaction SMILES: C[C:2]([O-:5])(C)C.[Na+].C1C=CC(P([C:20]2[C:29]([C:30]3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=[C:36]4[C:31]=3[CH:32]=[CH:33][CH:34]=[CH:35]4)=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=CC=2)C2C=CC=CC=2)=CC=1.C1C[O:56]CC1>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]>[CH3:2][O:5][C:24]1[CH:23]=[C:28]([CH:29]([CH3:20])[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:56])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Product: COc1cccc(C(C)C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
An oven-dried Schlenk tube containing a stir bar was charged with Pd2(dba)3 (6.9 mg, 0.0075 mmol, 1.5 mol %), ligand (0.018 mmol, 3.6 mol %), and NaOt-Bu (65 mg, 0.65 mmol). The Schlenk tube was evacuated and back filled with argon. THF (2 mL) was added followed by aryl halide (0.5 mmol), ketone (0.6 mmol or 1.0 mmol), and additional THF (1 !mL). The resulting red mixture was heated under argon at 70° C. until the starting halide had been consumed as judged by GC analysis. The Schlenk tube was cooled to room temperature, and diethyl ether (25 mL) and H2O (25 mL) were added. The aqueous layer was separated and extracted with diethyl ether (25 mL). The organic layers were combined, washed with brine (40 mL), dried over MgSO4, filtered, and concentrated. The crude product was then purified by flash chromatography on silica gel. Using 0.6 mmol of ketone and BINAP gave 107 mg (89% yield) of a colorless oil. 1H NMR (CDCl3, 250 MHz) δ 7.92-7.96 (m, 2H), 7.31-7.44 (m, 3H), 7.19 (t, J=7.0 Hz, 1H), 6.82-6.88 (m 2H), 6.72 (dd, J=8.3, 2.3 Hz, H), 4.64 (q, J=6.8 Hz, 1H), 3.73 (s, 3H), 1.52 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 250 MHz) 5200.1, 150.0, 143.0, 136.6, 132.7, 129.9, 128.7, 128.4, 120.2, 113.5, 112.2, 55.1, 47.9, 19.3; IR (neat, cm−1) 2975, 2932, 1682, 1597, 1583. Anal Calcd for C16H602: C, 79.97; H, 6.71. Found: C, 79.89; H, 6.62.