Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:16]([O:18][C:19]([CH3:21])=[CH2:20])=[O:17].O>N1C=CC=CC=1>[C:19]([O:18][C:16]([N:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3](=[O:13])[C:2]1([CH3:14])[CH3:1])=[O:17])([CH3:21])=[CH2:20]
Reactant: Cc1ccc2c(c1)NC(=O)C(C)(C)N2
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)OC(=O)N1c2ccc(C)cc2NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3,3,7-Trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.4 g, 2.1 mmol) were dissolved in 10 ml of anhydrous pyridine, and the stirred solution was treated at room temperature with 0.24 ml (2.2 mmol) of isopropenyl chloroformate. The mixture was stirred for 6 hours at room temperature and treated with water, the precipitate which formed was filtered off with suction, washed with water and dried. This gave 0.4 g (69%) of colorless crystals of melting point 185° C.
Reaction SMILES: CC1C=CC(S([O-])=O)=CC=1.[NH2:11][C:12]1[C:21]([C:22]([O:24]CC=C)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1>CS(C)=O.O.Cl.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>[NH2:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: C=CCOC(=O)c1c(N)nn2cc(F)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: Nc1nn2cc(F)cnc2c1C(=O)O
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
In an alternative method, 4-methylbenzenesulfinate (anhydrous, 1.2 eqv, 22.6 g, 127 mmol) was suspended in dry DMSO (20 vol, 500 ml). The stirred mixture was warmed to 30° C. under a nitrogen atmosphere. Upon complete dissolution Pd(PPh3)4 (2 mol %, 2.4 g, 2.1 mmol) was added. The mixture was stirred for 10 min at 25-30° C. after which time a turbid yellow solution was present. Allyl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (25 g, 105.8 mmol) was added portionwise, maintaining the temperature at 25-30° C. Once addition was complete the cloudy solution was stirred until the reaction was complete by HPLC (2-3 hrs). A heavy precipitate formed after 15 minutes post addition of the substrate. The mixture became thicker as the reaction proceeded. The reaction mixture was diluted with water (125 ml) and 2M HCl (66 ml) was added slowly, maintaining the temperature at 25-30° C. The slurry was stirred for 30 minutes, then filtered. The filtration was slow (2 hrs). The resulting solid was washed with water, then dried on the sinter. The solid was slurried in DCM (8 vol) for 1 hr. The solid was filtered (rapid filtration) and washed with DCM. The solid was re-slurried in chloroform (8 vol) for 1 hr. The acid was filtered and dried on the sinter. It was further dried in a vacuum oven at 50° C. for 24 hrs. The product was obtained as an off-white solid (18.6 g, 85%); 1H NMR (500 MHz, DMSO-d6) δ 12.14 (1H, brs), 9.31 (1H, dd), 8.69 (1H, m), 6.47 (2H, brS); 19F NMR (500 MHz, DMSO-d6) δ−153.65; MS (ES+) 197.1.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[N:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:30]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(Cl)n3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (39.5 mg, 90%).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:4]1=[O:27].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[ClH:1].[C:28]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:8][C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:4]1=[O:27])(=[O:30])[CH3:29]
Reactant: COc1ccc([C@H]2Cc3ccccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@H]2Cc3ccccc3N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
(cis)-3-Hydroxy-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one, monohydrochloride (1.27 g, 2.83 mmol) was slurried in 28 ml of acetic anhydride and heated at 100° C. under argon for 3 hours. The resulting solution was then concentrated and the residue dissolved in ethyl acetate. After crystallization commenced, hydrogen chloride saturated ether was added and the mixture was filtered to afford 1.25 g of the desired material as an off-white powder, melting point 215°-216° C.
Reaction SMILES: N.[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH:21]4[CH2:23][CH2:22]4)[N:15]=[C:14]3[CH2:24][CH3:25])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34]>C(O)C>[NH4+:13].[Br:2][C:3]1[C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([NH-:20])=[O:19])=[C:16]([CH:21]4[CH2:22][CH2:23]4)[N:15]=[C:14]3[CH2:24][CH3:25])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][S:33]([C:36]([F:39])([F:37])[F:38])(=[O:35])=[O:34]
Reactant: CCc1nc(C2CC2)c(C(N)=O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: N
Solvent: CCO
Product: CCc1nc(C2CC2)c(C([NH-])=O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Product: [NH4+]
Reaction time: 0.5 h
Yield: 194.6 %

Procedure:
Concentrated aqueous ammonia (0.2 ml) was added to a solution of the product of Example 6 (50 mg) in ethanol (1 ml) at room temperature. The mixture was stirred for 30 min, then the solvent was evaporated. The residue was triturated under ether (2 ml) and filtered to give the title compound as a colourless solid (50 mg), m.p. 135°-142°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[O:18]=[C:19]1[CH:23]=[CH:22][C:21](=[O:24])[N:20]1[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33](F)(F)F)[CH:26]=1.[CH:37]1[CH:42]=CC=C[CH:38]=1>>[C:29]([C:28]1[C:27]2[C:26](=[CH:38][CH:37]=[CH:42][CH:33]=2)[C:25]([N:20]2[C:21](=[O:24])[CH:22]3[CH:23]([C:13]4([CH3:16])[O:12][C:11]3([CH2:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:17])[CH2:15][CH2:14]4)[C:19]2=[O:18])=[CH:32][CH:31]=1)#[N:30]
Reactant: Cc1ccc(CC(=O)Nc2ccc(F)cc2)o1
Reactant: c1ccccc1
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Product: CC12CCC(CC(=O)Nc3ccc(F)cc3)(O1)C1C(=O)N(c3ccc(C#N)c4ccccc34)C(=O)C12
Temperature: 60 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Compound 216A (0.200 g, 0.858 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile (0.164 g, 0.616 mmol) were dissolved in benzene and heated at 60° C. for 14 h. The reaction was then cooled and concentrated in vacuo. The resulting orange oil was dissolved in EtOAc (15 mL) and 10% Pd/C (0.050 g) was added. Hydrogen was then introduced via a balloon. After 3 h, the reaction was filtered through Celite rinsing with EtOAc and concentrated in vacuo. The resulting crude material was purified by preparative TLC on silica eluting with 5% acetone in methylene chloride to give 0.166 g (54%) of compound 216B as a white solid. NMR spectroscopy showed only a single isomer which was determined to be exo by NOE experiments. HPLC: 95% at 3.200 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 484.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([F:32])[C:30]=1[F:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(F)c(F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4,5-difluorobenzoic acid: MS (APCl) m/z 440 (M+1).
Reaction SMILES: N[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][CH2:10][S:11](Cl)(=[O:13])=[O:12].[N:15]1C=CC=CC=1.Cl>O1CCCC1>[Cl:9][CH2:10][S:11]([NH:15][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2])(=[O:13])=[O:12]
Reactant: NOc1ccccc1
Reactant: O=S(=O)(Cl)CCl
Reactant: c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(CCl)Nc1ccccc1O
Reaction time: 8 h

Procedure:
O-Aminophenol (43.6 g, 0.40 mol) was dissolved in tetrahydrofuran (200 ml). Chloromethanesulfonyl chloride (61.8 g, 0,415 mol) was slowly added to the solution at room temperature, and the resultant solution, was stirred for 30 minutes. Pyridine (45 ml) was added to the solution, and stirring was continued overnight. The reaction mixture was acidified to pH=1 with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with sodium bicarbonate aq. and brine followed by drying over sodium sulfate. The solvent was removed by evaporation, and the residual oil was sitting at room temperature for 2 days to form crystals, which were collected by filtration to afford the titled product, 18.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][C:38]([CH3:40])=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH:38]([CH3:40])[CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: CC(C)=O
Product: CC(C)N1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoro-1-(1-methylethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[C-]#[N:20].[K+].[C:22]([OH:25])(=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([C:22]([NH2:20])=[O:25])[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:14](=[O:15])[O:16]2)=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1C(=O)O
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccc(Cl)cc2)OC(=O)c2ncccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-chlorobenzoyl)-2-pyridinecarboxylic acid (13 g), potassium cyanide (4.56 g), and acetic acid (30 mL) was heated at 120-125 C. in a sealed pressure bottle for 48 h. After cooling to ambient temperature, the mixture was poured into ice water. The precipitated solid was dissolved in ethyl acetate, washed with sodium bicarbonate saturated solution then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with ether. The formed solid was collected by filtration and dried to give 10.2 g of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide. A mixture of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide (5 g), 2-methyl-1,2-diamino propane (6.3 g), and toluene (80 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature. The precipitated material was collected by filtration and dried to give the title compound (2.4 g), m.p. 257-260° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.Cl.CO>C1COCC1>[NH2:18][CH2:17][C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CN

Procedure:
The solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbonitrile (0.130 g, 0.5 mmol) (Example 20) in THF (2 mL) is added borane dimethyl sulfide complex (0.055 mL, 0.55 mmol) dropwise, and the resulting mixture is stirred at reflux for 30 min. The reaction mixture is concentrated in vacuo and the residue is redissolved in THF (2 mL) and 0.5 M hydrogen chloride in methanol (1.1 mL, 0.55 mmol) is added dropwise. The reaction mixture is stirred at ambient temperature for 1.5 h. The mixture is concentrated in vacuo and the residue is purified by semi-preparative reverse phase HPLC to give 4-(5-aminomethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a yellowish solid; MS (ESI) m/z 271.9 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (s, 3 H), 1.59 (s, 3 H), 4.55-4.74 (m, 2 H), 5.99 (s, 1 H), 7.67-7.76 (m, 3 H), 7.82 (td, J=7.6, 1.5 Hz, 1 H), 8.29 (dd, J=7.7, 1.4 Hz, 1H), 8.52 (br. s, 1 H)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH:25]([CH3:29])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:2]1([CH2:1][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:26](=[O:27])[CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:29])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C(=O)Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reaction time: 0.83 h

Procedure:
A mixture of (4S)-(-)-4-benzyl-2-oxazolidinone (3.903 g, 22.0 mmol) in THF (23 ml) is cooled at -78° and butyl lithium (1.6M in hexane, 14.7 ml, 23.5 mmol) is added. The mixture is stirred for 50 min and then the portion of 2-phenylpropionic acid chloride (XL) from above, in THF (8 ml) is added dropwise to the mixture. The mixture is stirred for 1 hr at -78° and then allowed to warm to 20-25°. Saturated aqueous sodium bicarbonate solution (100 ml) is added and the phases separated. The aqueous phase is washed with ether and the combined organic phases are then washed several times with saturated aqueous sodium bicarbonate followed by a saline wash. The organic phase is dried over magnesium sulfate and concentrated. The resulting diastereomers are separated on silica gel eluting with ethyl acetate/hexane (7/93) followed by ethyl acetate/hexane (12/88). The appropriate fractions are pooled and concentrated to give (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLI, Isomer I, less polar isomer), NMR (CDCl3) 1.55, 2.79, 3.35, 4.09, 4.58, 5.12 and 7.30 δ; and (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLII, Isomer II, more polar isomer), NMR (CDCl3) δ 1.52, 2.58, 3.09, 4.08, 4.19, 4.75, 5.11, 6.95 and 7.31 δ.
Reaction SMILES: COC1C2C(=CC=C([C:13]([OH:15])=[O:14])C=2)C=CN=1.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][C:21]([NH2:27])=[CH:20]2>>[NH2:27][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:13]([OH:15])=[O:14])=[CH:26][CH:25]=2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: COc1nccc2ccc(C(=O)O)cc12
Product: Nc1cc2cc(C(=O)O)ccc2cn1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 12, Steps 2-3, using 6-bromoisoquinolin-3-amine. +ESI (M+H) 189.0; 1H NMR (400 MHz, DMSO-d6, δ): 13.15 (br. s., 1H), 8.94 (s, 1H), 8.20 (s, 1H), 7.91 (m, 1H), 7.62-7.59 (m, 1H), 6.78 (s, 1H), 6.14 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]#N)[C:10]2=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH2:19].S(=O)(=O)(O)[OH:21]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([OH:21])=[O:19])[C:10]2=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C#N)c(=O)n1-c1cc(F)cc(F)c1
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
1-(3,5-Difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.50 g, 6.20 mmol) was suspended in aqueous sulfuric acid solution (98% sulfuric acid 8 mL, water 8 mL), and the mixture was stirred at 120° C. for 10 hr. The reaction solution was cooled to room temperature and poured into water, and the precipitate was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (1.00 g, 61%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:22][CH2:23][CH2:24][C:25]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reactant: O=C(Cl)CCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(NC(=O)CCCl)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.62 g, 16.08 mmol) in benzene (100 mL) was added a catalytic amount of DMAP. An inert atmosphere was created and chloropropionyl chloride (2)(1.68 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 20 min, the reaction mixture was transferred to a separatory funnel containing 50% solution of sodium bicarbonate and was extracted with CH2Cl2 (3×250 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to give tert-butyl 6-[(3-chloropropanoyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a white solid in 99% yield: 1H NMR (DMSO, 500 MHz) δ 1.38-1.53 (m, 9H), 2.75-2.99 (m, 2H), 3.65-3.78 (m, 4H), 3.88-3.97 (m, 2H), 4.53 (brs, 2H), 6.88-6.96 (m, 1H), 7.15-7.22 (m, 1H), 7.31-7.37 (m, 1H), 9.72 (brs, 1H), 10.44 (brs, 1H) ppm.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](Cl)=[O:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.Br.Br.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:33]2[C:37]([CH3:38])=[N:36][N:35]=[C:34]2[CH2:39][NH2:40])=[C:23]([CH:32]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.CN(C)C=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:33]2[C:37]([CH3:38])=[N:36][N:35]=[C:34]2[CH2:39][NH:40][C:7](=[O:8])[CH2:6][N:5]2[C:4](=[O:10])[C:3]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]3[C:1]2=[O:15])=[C:23]([CH:32]=1)[C:24]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 69.4 %

Procedure:
To a solution of 2-phthalimidoacetyl chloride (1.5 g) in benzene (20 ml) and dimethylformamide (10 ml), 5-chloro-2-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (2.3 g) is added under ice cooling and stirring, and the temperature within the flask is gradually returned to room temperature. The reaction mixture is allowed to stand at room temperature, neutralized with saturated aqueous sodium bicarbonate, and shaken with ethyl acetate. The precipitated crystals are filtered, washed with methanol and dried to give 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.68 g) as crystals melting at 251°-253° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.18 (a) from 2,6-dichloroquinoline and piperazine-1-carboxylic acid tert-butyl ester. Crystallisation from methanol yields the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[C:24]1([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: O=C(O)C1=CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3=CCCCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol), cyclohex-1-enecarboxylic acid (73 mg, 0.58 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.2 mmol,) in dichloromethane (5 mL) was added phosphorus oxychloride (0.06 mL, 0.58 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 130 mg, yield: 60%.