Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][N:31]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1cnccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.146 g, 0.5 mmol) in Dichloromethane (DCM) (3 mL) was added triethyloxonium tetrafluoroborate (0.100 g, 0.525 mmol). The solution was then stirred, under argon, for 10 minutes before 2-pyrazinecarbohydrazide (commercially available from e.g. TimTec, J& W PharmLab and Akos Consulting, 0.083 g, 0.600 mmol) was added. The solution was then stirred for a further hour before the solvent was concentrated and n-butanol (3.00 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-direct automated HPLC, before the solvent was again evaporated in vacuo. The remaining solid was then triturated in ether before being dried in a vac-oven to yield the product in 0.056 g.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([NH:14][CH2:15][CH2:16]C)=[O:13])[CH:8]=[C:7]([CH3:18])[C:3]=1[C:4]([OH:6])=[O:5].[CH:19](N=C=O)(C)C.C(N=C=O)CC>>[CH3:18][C:7]1[CH:8]=[C:9]([NH:11][C:12]([NH:14][CH:15]([CH3:16])[CH3:19])=[O:13])[CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCNC(=O)Nc1cc(C)c(C(=O)O)c(C)c1
Reactant: CC(C)N=C=O
Agent: CCCN=C=O
Product: Cc1cc(NC(=O)NC(C)C)cc(C)c1C(=O)O

Procedure:
2,6-Dimethyl-4-(3-isopropyl-ureido)-benzoic acid was prepared in the same manner as 2,6-dimethyl-4-(3-propyl-ureido)-benzoic acid (see EXAMPLE 205) except isopropyl isocyanate was used in lieu of n-propylisocyanate.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4](SC)[S:5][CH3:6])#[N:2].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:9]1[N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:22])([F:23])[F:11])[CH:14]=2)[N:18]=[C:4]([S:5][CH3:6])[C:3]=1[C:1]#[N:2]
Reactant: NNCc1cccc(C(F)(F)F)c1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: CSc1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Yield: 79.4 %

Procedure:
8.5 g (0.05 mol) of 1,1-dicyano-2,2-bis(methylthio)-ethylene and 9.5 g (0.06 mol) of 3-trifluoromethylbenzyl-hydrazine (compare DE-OS (German Published Specification) No. 2,230,675) are stirred in 100 ml of ethanol at 20° C. for 15 hours. For working up, the solvent is removed in vacuo and the residue is triturated with petroleum ether. Filtration with suction gives 12.4 g (80% of theory) of 5-amino-4-cyano-3-methylthio-1-(3-trifluoromethylbenzyl)-pyrazole of melting point 142° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Br:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH:16]([CH3:20])[C:17]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1)=[O:18]
Reactant: OCC1CCCO1
Reactant: CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(Br)C(=O)OCC1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a 250 milliliter three-necked flask were added 0.15 mole of 2-(hydroxymethyl)tetrahydrofuran, 0.15 mole of triethylamine, and 100 milliliters of diethylether. The flask was immersed in ice, and 0.15 mole of 2-bromopropanoyl chloride introduced dropwise. The ice bath was removed, and the reaction stirred at ambient temperature for two hours. The mixture was extracted with an equal volume of water, and the organic phase dried over sodium sulfate. Decantation and solvent removal resulted in 2-tetrahydrofuranylmethyl 2-bromopropanoate in 94% yield.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]=[CH:7][CH:8]1[O:10][CH2:9]1>C(O)(C)(C)C>[OH:10][CH2:8][CH:8]([O:10][C:9]([CH3:9])([CH3:6])[CH3:7])[CH:7]=[CH2:6]
Reactant: C=CC1CO1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: C=CC(CO)OC(C)(C)C
Yield: 43.3 %

Procedure:
Concentrated sulfuric acid (18M; 0.1 mL; 2 mmol; 0.02 equiv.) was added to 80 mL of tert-butanol. Butadiene monoepoxide (8.05 mL; 100 mmol) was added and the reaction mixture was heated to reflux overnight (15 h) to completely consume butadiene monoepoxide by GC analysis. The reaction mixture was concentrated at reduced pressure and the residue was dissolved in ether (40 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic solution was dried (MgSO4) and concentrated, and the crude product was fractionated in vacuo, affording pure 1j (3.12 g; 22%), bp 42°-45°/1 mm Hg along with an impure fraction, 3.83 g, bp 45°-85°/1 mm Hg. 1H nmr (300 MHz, CDCl3): 5.797 (1H, ddd, J=6.29, 10.57, 17.07 Hz); 5.260 (1H, d, J=17.22 Hz); 5.144 (1H, d, J=10.50 Hz); 4.092 (1H, br q, J=5.76 Hz); 3.469 (1H, dd, J=4.45, 11.07 Hz); 3.399 (1H, dd, J=7.63, 11.14 Hz); 2.0 (1H, br s); 1.218 (9H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccsc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of thiophene-3-carboxylic acid (18.2 g) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (27.8 g) in small amounts on an ice bath. After stirring at room temperature overnight, the reaction solution was poured into water (1.5 L), and the resulting solid was collected by filtration and washed with water. After dissolving in ethyl acetate, and dried with anhydrous magnesium sulfate, the drying agent was removed by filtration, and evaporation in vacuo was carried out. The solid that was generated by dissolving the residue in ethyl acetate, and adding hexane were collected by filtration, and the crude product (16 g) of 5-bromo-thiophene-3-carboxylic acid was obtained as a colorless solid.
Reaction SMILES: [OH:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:18]O>S(=O)(=O)(O)O.COC(OC)(C)C>[CH3:18][O:16][C:15]([CH:11]1[CH2:12][C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][OH:1])=[CH:8][CH:7]=2)[CH2:10]1)=[O:17]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OO)cc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)OC
Product: COC(=O)C1CC(=O)N(c2ccc(OO)cc2)C1
Yield: 84 %

Procedure:
In a 10 14-necked flask equipped with a reflux condenser, a thermometer, and a mechanical stirrer, the crude (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is dissolved in a mixture of 5000 ml of methanol, 24 ml of concentrated sulfuric acid and 400 ml of 2,2-dimethoxypropane and stirred under reflux during 2 h. For the working-up, the reaction solution is reduced to half of its volume by distillation, then transferred into a 20 l vessel. Under stirring at 40° C., a mixture of 2500 ml of water/ice (1:1) is added. Crystallisation started immediately, and, thereupon, the fine white crystals are collected on a filter funnel. They are washed with total 2000 ml of cold water until the filtrate, at the beginning brownish-rose, becomes colorless and neutral. The well pressed and pre-dried product from the filter funnel is dried under reduced pressure to yield 980 g (84% of theory, 2 steps) of the (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[CH:11][CH:12]=2)[C:7]1=[O:27])C.[OH-].[Na+]>C(O)C>[Cl:24][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[CH:11][CH:12]=2)[C:7](=[O:27])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[N:15]=1
Reactant: CCOC(=O)Cn1nc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn(CC(=O)O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A suspension of [4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1-oxo-1H-phthalazin-2-yl]-acetic acid ethyl ester (0.65 g, 1.54 mmoles), prepared as described in example 44, in ethanol (30 ml) was added with concentrated NaOH (3 ml). The mixture was stirred overnight at room temperature, then dried, taken up in water and washed twice with CH2Cl2. The aqueous phase was acidified with concentrated HCl. The precipitate was filtered and dried over P2O5 at 60° C., then crystallised from CH3OH (25 ml) and the filtrate was dried at 45° C. to give 0.36 g of the title compound (yield: 60%). m.p.: 221.4-222.4° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:25]#[N:26])[CH3:24])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2[N:16]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[C:25]#[N:26])[O:27][C:14]=2[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)C(NC(=O)CCCCCC(C)C#N)c2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(CCCCCC(C)C#N)oc2-c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
15 g of phosphorus oxychloride is added with stirring to a solution of 13.8 g of (RS)-1,2-bis(4-methoxyphenyl)-2-(7-cyanooctanamido)ethanone in 65 cm3 of toluene, and the mixture is heated to 80° C. for 4 hours. The solution is poured onto 50 g of ice, the toluene phase is separated after settling has taken place and the aqueous phase is extracted with twice 50 cm3 of ethyl acetate. The combined organic extracts are washed with water (3 times 20 cm3) and with 30 cm3 of saturated aqueous sodium chloride solution. After drying over-sodium sulphate, the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column 2.8 cm in diameter containing 100 g of silica gel (50 to 200). The column is eluted, collecting 50 cm3 fractions, with 1.8 liters of diisopropyl ether. The fractions emerging at between 0.3 liter and 1.8 liters are concentrated under reduced pressure (0.2 kPa). 12.4 g (93%) of (RS)-7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methylheptanenitrile are obtained in the form of a yellowish oil, which is used directly in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[S:24][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:21](O)=[O:22])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[C:12]=3[C:4]=2[CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:9]2[C:8]3[CH2:7][CH2:6][C:5]4[S:24][C:2]([Br:1])=[CH:3][C:4]=4[C:12]=3[N:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:10]=2)=[O:22])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCc1sc(Br)cc1-2
Product: O=C(NN1CCCCC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCc1sc(Br)cc1-2
Yield: 42 %

Procedure:
The same procedure described in the preparations a) and b) of Example 3.1. was used to react the 7-bromo-1-(2′,4′-dichlorophenyl)-4,5-dihydro-1H-thieno[2,3-g] indazol-3-carboxylic acid prepared in the Example 2.2 with 1-aminopiperidine. The purification by flash chromatography (oil ether/ethyl acetate 6/4) has given the compound N-piperidinyl-7-bromo-1-(2′,4′-dichlorophenyl)-4,5-dihydro-1H-thieno[2,3-g]indazol-3-carboxamide as white solid with a 42% yield. Rf=0.33 (oil ether/ethyl acetate 6/4); m.p.: 145° C.;
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:51]([OH:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=1[F:50]
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 21q (136 mg, 0.18 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.1 mL, 0.87 mmol) and 10% Pd/C (20 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature for 4 hours under H2 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 21 as colourless oil (34 mg, 39.3%, HPLC: 97.27%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 517.2 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.43 (d, 1H), 7.40-7.23 (m, 2H), 6.96 (m 1H), 6.87 (m, 1H), 5.33 (s, 1H), 4.93 (s, 2H), 4.58 (s, 1H), 4.05 (s, 2H), 3.98 (d, 1H), 3.84 (s, 3H), 3.76 (d, 1H), 3.53 (d, 1H), 3.42 (m, 3H), 1.18-1.13 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:25]3[CH2:27][CH2:26]3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: OB(O)C1CC1
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C3CC3)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 100 °C
Yield: 28.4 %

Procedure:
To a mixture of (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol), cyclopropylboronic acid (6.59 mg, 0.077 mmol) and potassium phosphate (0.033 g, 0.153 mmol) in toluene/H2O (1.5 mL/0.050 mL) under nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (5.91 mg, 5.11 μmol) was added. The reaction was heated at 100° C. for 30 min in a heavy walled sealed tube under microwave irradiation. Additional cyclopropylboronic acid (6.59 mg, 0.077 mmol) was added and the reaction was heated at 100° C. for 2 more hours. The mixture was purified by HPLC to give the titled compound (5.1 mg) as a white solid. LCMS m/z=353.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)cc(Br)c(=O)n1Cc1ccc(OC)cc1

Procedure:
A solution of ethyl 5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (3.0 g, 10.7 mmol), 4-methoxybenzyl chloride (4.19, 26.74 mmol) and potassium carbonate (4.43 g, 32.09 mmol) in dimethylformamide (40 ml) was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was again washed with brine, separated, dried over Sodium sulfate, filtered and concentrated under reduced pressure. The residue was finally purified by flash column chromatography to afford ethyl 5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (2) as off white solid. Yield: 1.2 g, 28%; MS (ESI) m/z 399.99 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.11 (d, J=8.64 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.11 (s, 2H), 4.27 (q, J=7.12 Hz, 2H), 3.72 (s, 3H), 1.13 (t, J=7.12 Hz, 3H).
Reaction SMILES: ClC1C=C(N2C(C3C=CC=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[C:35]([C:36]3[CH:41]=[C:40](F)[CH:39]=[C:38]([Cl:43])[CH:37]=3)=[CH:34][C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])=[N:32]2)[CH:27]=[CH:28][C:29]=1F>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:43])[CH:37]=3)=[CH:34][C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])=[N:32]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 74A in analogy to the synthesis of the compound of Example 1. 110 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn2ccc(OCCCN3CCOCC3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
To a suspension of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.218 mmol) obtained in Example 31-B-(i) and potassium carbonate (60.3 mg, 0.436 mmol) in DMF (4 mL), was added 4-(3-chloropropyl)morpholine (71.3 mg, 0.436 mmol) obtained above and the mixture was stirred for 5 h at 60° C. To the reaction mixture, were added EtOAc (20 mL) and saturated aqueous solution of sodium bicarbonate (15 mL). The organic layer was separated and then aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL) and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=30/70→60/40) to give the title compound (128 mg, quant) as a colorless solid
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1)(C)(C)C.[OH-:34].[Na+]>Cl>[NH2:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:34])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1
Reactant: CC(C)(C)NC1=NC2(CS1)CC(c1ccccc1)Oc1ccc(-c3cccc(C#N)c3)cc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (30 mg, 0.066 mmol) in concentrated HCl (5 mL) was stirred at 100° C. for 2 h. Aqueous NaOH (6 N) was added until pH=8. The mixture was extracted with EtOAc and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 73%).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]([CH:22]2[CH2:24][CH2:23]2)[C:19](=[O:21])[CH3:20])[CH2:10][C@@H:9]1[CH3:25])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:22]1([N:18]([C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C@@H:9]([CH3:25])[CH2:10]2)[C:19](=[O:21])[CH3:20])[CH2:23][CH2:24]1
Reactant: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)N(Cc2ccccc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)Nc2ccccc21
Yield: 92.2 %

Procedure:
To a solution of Cis-N-(1-benzyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-cyclopropyl-acetamide (3.8 g) in ethanol (150 ml), ammonium formate (7.2 g) and few milligrams of palladium on charcoal (10% Pd/C) were added. The mixture was heated under reflux for 2 hours. After cooling the mixture was filtered on celite and the solvent was removed under reduce pressure to give Cis-N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-acetamide (2.56 g, 92.4% yield) which was not purified.