Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2>[Ni].CO>[NH2:5][C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[C:3]([C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2](=[O:6])[CH3:1]
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCCN(C)C
Agent: [Ni]
Solvent: CO
Product: CC(=O)C(=C(N)c1ccccc1)c1[nH]c2ccccc2c1CCCN(C)C

Procedure:
A mixture of 3.6 grams (0.01 mole) of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-(3-dimethylamino propyl)-1H-indole and 0.75 grams of Raney nickel in 75 milliliters of methanol is hydrogenated at 50 psi and 25° C. until thin layer chromatography shows no remaining starting material (18 hours). The mixture is filtered through celite and the celite washed with methanol. The combined methanol filtrates are evaporated in vacuo, and the resulting oil is crystallized from ethanol to give 4-amino-3-[3-(3-dimethylamino propyl)-1H-indol-2-yl]-4-phenyl-3-buten-2-one, (m.p. 268°-269° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].O=[C:16]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]([OH:19])=[O:18]>C1C=CC=CC=1.O1CCOCC1>[C:17]([C:16]1([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:7]2[NH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:1][CH3:2])([OH:19])=[O:18]
Reactant: CCNCCc1c[nH]c2ccccc12
Reactant: O=C(O)CCCC(=O)C(=O)O
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCN1CCc2c([nH]c3ccccc23)C1(CCCC(=O)O)C(=O)O
Yield: 40 %

Procedure:
5 g of N-ethyl-tryptamine (i.e., 3-(2-ethylaminoethyl)-indole) were dissolved in 100 ml of absolute benzene, and a solution of 4.70 g of α-keto-adipic acid in 50 ml of absolute dioxane was added thereto at room temperature. The mixture was refluxed for 20 hours. After the reaction was completed, the mixture was evaporated to remove solvent. The residue thus obtained was recrystallized from ethanol, whereby 3.51 g of 1,2,3,4-tetrahydro-1-carboxy-1-(3-carboxypropyl)-2-ethyl-β-carboline were obtained. Yield: 38.0%
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[CH:2]=[CH2:3].[N+:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CCOCC>[N+:8]([CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O-:10])=[O:9]
Reactant: C=CC(=O)OCC
Reactant: CCCCCC[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCC(CCC(=O)OC)[N+](=O)[O-]

Procedure:
A suspension of ethyl acrylate, 1-nitrohexane, K2CO3, and Aliquat 336 (6 drops) is sonicated for 5 h. To the reaction is added Et2O. The reaction mixture is filtered, extracted with brine, dried over Na2SO4 (anhydrous), filtered, and concentrated under reduced pressure to give a yellow liquid. The product is purified by column chromatography to give methyl 4-nitrononanoate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14](O)=[O:15])[CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN[C@H](CO)C1
Temperature: 90 °C
Yield: 100.5 %

Procedure:
To a stirred suspension of (S)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (5.00 g, 21.7 mmol) in THF (40 mL) was slowly added 1.0 M borane-THF complex solution (32.6 mL, 32.6 mmol). The reaction was heated to 90° C. and stirred under reflux for 2 hours. The reaction mixture was removed from the heat before a further 1.5 equivalents of 1.0 M borane·THF complex solution (32.6 mL, 32.6 mmol) was added. The reaction was re-heated to 90° C. and stirred under reflux for a further 2 hours. The reaction was cooled to 0° C. and quenched by the slow addition of MeOH. The reaction mixture was then concentrated in vacuo. The white solid obtained was dissolved in THF (30 mL), cooled to 0° C. and slowly added a 2.0M solution of LiAlH4 in THF (27 mL, 54.0 mmol). The reaction was heated to 90° C. and stirred under reflux for 2 h. A further portion of 2.0M solution of LiAlH4 in THF (27 mL, 54.0 mmol) was added and the reaction stirred under reflux for 4 h and then at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched by the slow addition of 1.0M aq NaOH solution until the exothermic reaction subsided. The resulting gel was diluted with THF and the solids filtered off. The filtrate was then concentrated in vacuo to afford (S)-(4-methyl-piperazin-2-yl)-methanol (2.84 g, 101% crude yield) as a colourless oil.
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (295 mg, 0.865 mmol), in 3.5 mL of 1,4-dioxane was added DDQ (216 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (998 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 60 mg (20%) of the title compound as a white solid. mp 199°-201° (decomp.) FDMS m/e=339. α[D]589 =+35.98 (c=0.67, chloroform).
Reaction SMILES: [Cl:1][C:2]([C:11]#[N:12])=[CH:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].S(Cl)([Cl:22])(=O)=O>C(Cl)Cl.ClC(Cl)C>[Cl:10][C:5]([S:4][C:3]([Cl:22])=[C:2]([Cl:1])[C:11]#[N:12])=[C:6]([Cl:9])[C:7]#[N:8]
Reactant: N#CC(Cl)=CSC(Cl)=C(Cl)C#N
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: N#CC(Cl)=C(Cl)SC(Cl)=C(Cl)C#N
Temperature: 70 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
3.3 g of 1,2-dichloro-2-cyano-vinyl 2-chloro-2-cyano-vinyl sulphide were dissolved in 20 ml of methylene chloride, 2 g of potassium carbonate were added, and 2.15 g of sulphuryl chloride in 10 ml of dichloroethane were added dropwise at room temperature. The mixture was stirred at 70° C. for 12 hours and filtered, the filtrate was washed with water and concentrated and the resulting oil was chromatographed. 1.7 g of bis-(1,2-dichloro-2-cyano-vinyl) sulphide were obtained as an oil, which was identical to the product from Example 8.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([OH:24])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][C:21]([OH:24])([CH3:25])[CH2:20][CH2:19]3)=[CH:16][N:17]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: CC1(O)CCN(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(N3CCC(C)(O)CC3)cn2)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (902 mg, 4.04 mmol), 1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-ol (761 mg, 3.67 mmol), Xantphos (159 mg, 275 μmol) and cesium carbonate (3.59 g, 11 mmol) in dry dioxane (10 ml) was vacuum de-gassed and placed under an argon atmosphere. To this mixture was added tris(dibenzylideneacetone)dipalladium (0) (38 mg, 36.7 μmol) and the vacuum de-gas cycle was repeated. The material was heated at 90° C. (oil bath) with vigorous stirring overnight. The flask was cooled to ambient and the contents were filtered through a plug of celite, rinsing well with dioxane, and concentrating. The product was purified by preparative HPLC on silica gel, using a gradient of 5% to 70% ethylacetate/hexane. This provided the desired product as a light yellow solid (807 mg 62.9%). (M+H)+=350, 352 m/e.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C)C=O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH:15]([CH3:17])[CH3:16])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: COC1=CN=C(CO)CC1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(CO)cc1OC(C)C
Reaction time: 0.12 h
Yield: 32229.2 %

Procedure:
To a stirred suspension of 2-hydroxymethyl-5-methoxy-4-pyridone (1.00 g, 6.45 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in mineral oil; 0.26 g, 6.5 mmol). The fizzy mixture was stirred for 5-10 minutes before adding, dropwise, 2-iodopropane (0.65 mL, 6.5 mmol). The reaction was stirred at room temperature overnight and then at reflux for 4 hours. At this time, additional sodium hydride (0.07 g, 1.8 mmol) and 2-iodopropane (0.16 mL, 1.6 mmol) were added and the mixture was heated at reflux for another 4 hours. The reaction was then concentrated and partitioned between methylene chloride and aqueous sodium carbonate solution. The resulting biphasic mixture was filtered through Celite to remove a small amount undissolved solid. The organic layer of the filtrate was dried (sodium sulfate) and concentrated to afford a dark brown oil. This material was purified by flash chromatography over silica (methylene chloride/methanol) to afford 410 g (32%) of product as a crystalline light brown solid: 1H NMR (CDCl3) δ 7.92 (s, 1H), 6.61 (s, 1H), 4.54 (sept, J=6.2 Hz, 1H), 4.53 (s, 2H), 3.79 (s, 3H), 1.29 (d, J=6.0 Hz, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[CH:4](C(OCC)=O)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].B(O)(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]([F:17])([F:18])[C:3](=[O:16])[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OB(O)O
Product: CCOC(=O)CCC(=O)C(F)(F)F
Yield: 32.7 %

Procedure:
45 g of the product of Step A, 10.3 g of boric acid and 1 g of p-toluenesulfonic acid were heated at 180° C. for 3 hours and the mixture was poured into ice and extracted with ethyl acetate. The mixture was decanted, dried and concentrated under reduced pressure and the residue was distilled to obtain 10.8 g of expected product.
Reaction SMILES: [OH:1][C:2]1([C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O>[OH:1][C:2]1([C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccccc3[nH]c2=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccccc2cc1C1(O)CCNCC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxy-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (300 mg, 0.87 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL). The reaction was stirred 30 min and concentrated. The residue was dissolved in water, extracted with dichloromethane (2×) which were discarded. The aqueous was made basic with solid potassium carbonate. The resulting solid was filtered to give 145 mg (68%) as a white powder. Mass spec.: 245.35 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[OH:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:25][CH3:26])[CH:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[O:18]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2cc(Cl)c(Br)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(Br)cc2c1=O
Temperature: 80 °C

Procedure:
33 g of the above compound were added to 50 cm3 of Dowtherm, heated at 250° C. and stirred in a round-bottomed flask equipped with a descending condenser which enabled the alcohol formed in the reaction to be collected; the reaction was complete after heating for 15 minutes. After cooling, the contents of the round-bottomed flask were taken up in 200 m3 of ethyl acetate. The solid was separated and recrystallised from dimethylformamide. 27.9 g of 6-bromo-7-chloro-3-ethoxycarbonyl-4-hydroxy-quinoline, m.p. 368°-370° C. (decomposition), were obtained. 13 g of 6-bromo-7-chloro-3-ethoxycarbonyl-4-hydroxyquinoline, 11 g of potassium carbonate and 100 cm3 of dimethylformamide were heated at 110° C. for 1 hour, whilst stirring. After cooling to 80° C., 16 cm3 of ethyl iodide were added to the mixture which was stirred and heated at 110° C. for 4 hours. After concentration to dryness in vacuo, the residue was taken up in 200 cm3 of water. The mixture was extracted with chloroform (3×100 cm3), and the combined organic extracts were washed with water, dried (MgSO4) and concentrated to dryness. The residue, recrystallised from 95 cm3 of isopropanol, gave 10 g of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-3-ethoxycarbonylquinoline, m.p. 166° C. 10 g of the above ester were added to an aqueous-alcoholic solution of sodium hydroxide (NaOH:2.25 g, water:50 cm3, ethanol:100 cm3). The mixture was heated under reflux for 30 minutes. The solution was concentrated to dryness in vacuo. The residue was suspended in 100 cm3 of water. The solution was acidified by adding 3.4 cm3 of acetic acid. The solid was separated and recrystallised from DMF (90 cm3). 8.1 g (89%) of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 320° C. (decomposition), were obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][C:21]([OH:23])=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.S(O)(O)(=O)=O.[NH2:41][C:42]([NH2:44])=[NH:43].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][C:21]([NH:43][C:42]([NH2:44])=[NH:41])=[O:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)N
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NC(=O)CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid (0.30 grams, 0.80 mmole) and carbonyl diimidazole (0.13 gms, 0.90 mmole) in 30 mL DMF was stirred for three hours at room temperature. Guanidine sulfate (90 mg) was added, followed by 0.1 ml diisopropylethylamine, and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and the resulting white crystals were collected by filtration, washed with water, and dried under vacuum to afford 190 mg of N-[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-guanidine, M+H=372.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.CS([Cl:27])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][Cl:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: OCc1ccc(OCC(F)(F)F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10 mL) was cooled to 0° C. and treated with triethylamine (91 mg, 1.15 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was then diluted with DCM (10 mL) and washed with 1 M hydrochloric acid (10 mL) and sat. NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford the title compound (260 mg, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J=2.0 Hz, 1H), 7.32 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.42 (q, J=8.0 Hz, 2H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)OC)cnc12
Yield: 82 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.8 g, 9.9 mmol) obtained in Example 21, step 2 and 2,5-dimethylaniline (1.5 mL, 11.8 mmol), the title compound (2.99 g, 81%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[O:28][N:27]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 479.0355 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 31.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.43 g, 3 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.49 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[OH-].[Na+].[Cl:12][CH2:13][C:14](Cl)=[O:15]>O>[Cl:12][CH2:13][C:14]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)=[O:15]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCl)N[C@H]1CC[C@H](O)CC1

Procedure:
15.1 g. (0.1 mole) trans-4-aminocyclohexanol hydrochloride are suspended in 100 ml. water and adjusted to a pH of 12.5 by the addition of 50 ml. 2N aqueous sodium hydroxide solution. 9.5 ml. (0.12 mole) chloroacetyl chloride are then added dropwise thereto and the pH maintained at 12 to 12.5 by the simultaneous dropwise addition of 2N aqueous sodium hydroxide solution. After the end of the reaction, the reaction mixture is extracted with n-butanol and the organic phase is distilled off in a vacuum. The residue is again dissolved in ethanol, filtered, evaporated and triturated with diethyl ether. After filtering off with suction, there are obtained 12.9 g. of the title compound, i.e. 67% of theory; m.p. 149°-151° C.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[C:4]2[C:30]([CH3:36])([C:31]([O:33]CC)=O)[C:29](=[O:37])[NH:28][C:5]=2[N:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[N:10]=2)[N:8]=1>>[NH2:2][C:3]1[C:4]2[C:30]([CH3:36])([C:31]([NH2:1])=[O:33])[C:29](=[O:37])[NH:28][C:5]=2[N:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:24])([F:23])[F:25])[N:10]=2)[N:8]=1
Reactant: N
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Product: CC1(C(N)=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 50 °C

Procedure:
Ammonia (2.0M in MeOH, 11 mL, 22 mmol) was added to ethyl 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 157, (150 mg, 0.289 mmol, single enantiomer from SFC separation on Chiralpak AD column). The resultant mixture was heated at 50° C. for 16 hours. The reaction solution was then concentrated in vacuo, and the residue purified by preparative TLC using 5% MeOH in DCM (with 0.5% NH4OH) as the eluent to give the indicated compound. 1H NMR (500 MHz, DMSO-d6): δ 8.66 (d, J=8.7 Hz, 1H); 8.02 (d, J=1.4 Hz, 1H); 7.45 (br s, 1H); 7.27 (dd, J=8.7, 1.7 Hz, 1H); 7.19 (br s, 1H); 6.79 (br s, 2H); 4.82 (t, J=6.8 Hz, 2H); 2.95-2.85 (m, 2H); 1.56 (s, 3H). m/z=504.1 (M+H).