Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:42]([O:44]C)=[O:43])(=[O:7])=[O:6])[CH3:4]>CO.O>[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:42]([OH:44])=[O:43])(=[O:6])=[O:7])[CH3:4]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 65 °C
Yield: 61.9 %

Procedure:
Potassium hydroxide (0.364 g, 6.50 mmol) was added to a suspension of methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.805 g, 1.299 mmol) in methanol (12.99 mL) and water (4.33 mL). The mixture was heated to 65° C. for 3 d. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (5 mL), and acidified to pH 4-5 with 2N HCl. The resulting precipitate was collected by filtration and dried to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.487 g, 59% yield) as a tan solid. MS (m/z) 606.2 (M+H+).
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C[Li]>CCOCC>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]1[CH2:4][CH:2]=1
Reactant: OCCCCCCCC1(Br)CC1(Br)Br
Agent: [Li]C
Solvent: CCOCC
Product: OCCCCCCCC1=CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
A solution of 1.0 g 1,1,2-tribromo-2-(7-hydroxyheptyl)cyclopropane (2.5 mmol) in 25 ml of ether was treated at −78° C. with 7.2 ml of methyllithium (1.4 M, 10 mmol). After 5 minutes, the reaction mixture was warmed to 0° C. and held at this temperature. The reaction was quenched with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 240 mg of 1-(7-hydroxyheptyl)-cyclopropene.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[O:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1>>[O:26]1[CH2:29][CH:28]([NH:30][C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:23])[CH2:27]1
Reactant: NC1COC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NC3COC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and oxetan-3-yl amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:26][C:22]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=3)[NH:9]2)[CH:3]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(N)C(=O)O
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NC(C)(C)C(=O)O)c1)N2
Temperature: 25 °C

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinoline (329.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) 2-methyl-2-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-propionic acid (104.8 mg, 29%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 353.1.
Reaction SMILES: CC[O-].[Na+].O=[C:6]([CH2:13][C:14](=O)[CH2:15][CH2:16]C)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:19][NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH3:19][N:20]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:13]([CH2:14][CH2:15][CH3:16])=[N:21]1
Reactant: CCCC(=O)CC(=O)CC(=O)OCC
Reactant: CNN
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)n(C)n1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
76.5 g of 20% strength by weight sodium ethylate solution were initially introduced into a 250 ml 4-necked flask and 41.9 g of ethyl 2,4-diketoheptanecarboxylate were added in the course of 15 minutes. The solution thus prepared was added to a mixture of methylhydrazine (10.4 g), acetic acid (13.5 g) and ethanol (20 ml) at an internal temperature of 30 to 40° C. in the course of 45 minutes. When the addition was complete, the mixture was subsequently stirred at room temperature for a further hour and the ethanol was then distilled off. 100 ml of toluene and 100 ml of water were then added, the phases which form were separated and the aqueous phase was extracted twice more with 50 ml of toluene each time. The combined toluene extracts were reextracted with 100 ml of water, dried and concentrated under a slight vacuum. 31 g of isomer-free ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate having a boiling point of 125 to 128° C. under a pressure of 13 mm were obtained by fractional distillation. This corresponds to a yield of 75% of theory. The undesirable isomer ethyl 1-methyl-5-n-propyl-pyrazole-3-carboxylate was obtained as a second fraction in a yield of 6.2 g (=15% of theory). The boiling point of this isomer was 166 to 168° C. under a pressure of 13 mm.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=O.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14].C(N(CC)CC)C>C(O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3[N:18]=[C:16]([CH2:15][C:13]#[N:14])[S:17][C:2]=3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: N#CCC(N)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCc1nc2c(s1)Cc1cc(Cl)ccc1-2

Procedure:
1 g (4 mmol) of 2-bromo-5-chloroindan-1-one is stirred with 450 mg (4.5 mmol) of 2-cyanothioacetamide and 0.55 ml (4 mmol) of triethylamine in 10 ml of dry ethanol at room temperature for 4 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography on silica gel with ethyl acetate/n-heptane 1/1. (6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)acetonitrile is obtained with a melting point of 134° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:44])[CH2:10][C:11]1[CH:43]=[CH:42][CH:41]=[CH:40][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH:31]1[CH2:32][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=4[CH2:10][C:9]([NH2:8])=[O:44])[C:20]([CH3:21])=[CH:19][N:18]=3)=[CH:28][CH:27]=2)[CH2:30]1
Reactant: Cc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C3CNC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.1 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A123) (0.087 g, 0.17 mmol) in DCM (3 mL) and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 solution (5 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried. The resulting residue was purified by semi preparative HPLC to give the title compound 32 as a light tan solid (7.6 mg, 10%); 1H NMR (300 MHz, d4-MeOH) δ 8.12 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.18-7.28 (m, 4H), 4.31-4.39 (m, 2H), 4.19-4.27 (m, 3H), 3.66 (s, 2H), 3.13-3.18 (m, 2H), 2.96-3.01 (m, 2H), 2.12 (s, 3H). LCMS-B: rt 4.725 min; m/z 402 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][N:7]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cnc(NCC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])cnc1NCC1CC1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of N-(cyclopropylmethyl)-3,5-dinitro-2-pyridinamine (1.17 g, 4.92 mmol) in EtOAc (50 mL) at room temperature was added Pd/C (394 mg, 0.25 mmol, 10% grade). The mixture was placed in a Parr apparatus under 35 psi H2. The mixture was shaken overnight. The reaction was filtered over Celite and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2.5% MeOH+1% NH4OH aq] in CH2Cl2) to provide 792 mg of the title compound N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine (77.3% yield from N-(cyclopropylmethyl)-3,5-dinitro-2-pyridinamine). 1H-NMR (400 MHz, CDCl3): δ 0.31 (m, 2H), 0.61 (m, 2H), 1.14 (m, 1H), 3.34 (br s, 2H), 3.42 (dd, J=5.3, 7.2 Hz, 2H), 5.15 (br s, 1H), 7.62 (d, J=2.5 Hz, 1H), 8.73 (d, J=2.5 Hz, 2H). MS (ESI) (M+H)+: 209.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1oc(-c2ccc(O)cc2)cc1C=O
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 4-hydroxyphenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound (1.6 g, 35%) as a yellow crystal.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]Cl>C1(C)C=CC=CC=1>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1
Reactant: ClCc1cccs1
Reactant: SC1=NCCS1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1csc(CSC2=NCCS2)c1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
To a stirred solution of 1.3 grams (0.011 mole) of 2-mercaptothiazoline in 20 ml of toluene was added 1.1 grams (0.011 mole) of triethylamine, followed by 1.5 grams (0.011 mole) of 2-thienylmethyl chloride. Upon completion of addition the reaction mixture was heated under reflux for five hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give 2.4 grams of 2-(2-thienylmethylthio)-4,5-dihydrothiazole as an oil, Compound No. 22 of Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Yield: 19.9 %

Procedure:
2-(6-Chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.73 g, 1.17 mL, 15.2 mmol). After 72 h the mixture was concentrated in vacuo, the residue diluted in dichloromethane, and then and re-concentrated in vacuo. Purification by chromatography (silica, Analogix 40 g cartridge, 0-5% methanol in dichloromethane, gradient over 15 min) gave 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 36.7 μmol, 20.0%) as an off-white powder. MS (M+Na)+=431; 1H NMR (CDCl3) δ: 9.67 (br. s., 1H), 9.19-9.31 (m, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.21-7.26 (m, 1H), 4.41-4.55 (m, 1H), 4.34 (d, J=7.2 Hz, 2H), 1.43 (d, J=6.4 Hz, 6H), 1.04-1.21 (m, 1H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([CH3:10])[CH2:8][NH2:9])[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([CH3:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]2[CH:32]=[C:24]([C:21]3[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=3)[CH:25]=[N:26][CH:27]=2)[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(CN)c1cn(C)c(-c2ccccc2)n1
Product: CC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1cn(C)c(-c2ccccc2)n1
Yield: 16 %

Procedure:
This compound was synthesized from 2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (10 mg, yield 16%). 1H NMR (400 MHz, CDCl3) δ 9.40 (d, J=2.1 Hz, 1H), 9.31 (d, J=2.1 Hz, 1H), 9.16-9.15 (m, 1H), 8.87-8.86 (t, J=2.1 Hz, 1H), 7.62-7.59 (m, 2H), 7.42-7.40 (m, 3H), 6.81 (s, 1H), 4.02-3.96 (ddd, J=12.9 Hz, 6.2 Hz, 4.3 Hz, 1H), 3.75 (s, 3H), 3.42-3.35 (ddd, J=12.9 Hz, 9.4 Hz, 3.2 Hz, 1H), 3.15-3.10 (m, 1H), 1.40-1.38 (d, J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:18][CH3:19])[C:9]=2[CH:8]([C:20]([CH3:22])=[CH2:21])[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:22][C:20]([CH:8]1[C:9]2[C:10]3[C:15](=[C:14]([CH2:18][CH3:19])[CH:13]=[CH:12][CH:11]=3)[NH:16][C:17]=2[C:5]([CH2:23][CH3:24])([CH2:4][C:3]([OH:25])=[O:2])[CH2:6][CH2:7]1)=[CH2:21]
Reactant: C=C(C)C1CCC(CC)(CC(=O)OC)c2[nH]c3c(CC)cccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C(C)C1CCC(CC)(CC(=O)O)c2[nH]c3c(CC)cccc3c21
Reaction time: 24 h
Yield: 91.5 %

Procedure:
The 4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid methyl ester (1.72 g, 5.08 mmol), prepared in Step (b), derived from the less polar ketone, and 7.11 mmol of K2CO3 (0.983 g) were refluxed under nitrogen in 40.6 ml of MeOH containing 5.1 ml of water. After 24 hours, most of the methanol was removed in vacuo and the residue was dissolved in 15 ml of water. It was acidified to pH~1 with 3M HCl (aq.) and extracted with 4×40 ml of ether. Drying (MgSO4) and flash chromatography afforded 1.51 g (4.65 mmol, 91%) of yellow oil. The compound was recrystallized from 2:1 petroleum ether/benzene to give 988 mg of white powder which was dried at 78° C. (high vacuum, phosphorous pentoxide) m.p. 133.5°-135° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[Cl:24][CH2:25][C:26]#[C:27][CH2:28][OH:29]>C(Cl)Cl.C(Cl)Cl.O>[C:6]([Si:10]([O:29][CH2:28][C:27]#[C:26][CH2:25][Cl:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: OCC#CCCl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of imidazole (691 mg, 10.2 mmol) and tert-butylchlorodiphenylsilane (2.65 ml, 10.1 mmol) in DCM (15.3 mL) at 0° C. was added 4-chlorobut-2-yn-1-ol (824 μL, 9.18 mmol). After 2 h of stirring at rt it was diluted with DCM/water and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue dissolved in dioxane and reconcentrated (2×) then used directly without further purification.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd].[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11]
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN)cc1NC=O
Yield: 89.7 %

Procedure:
A solution of {5[(1R)-2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-[({[2-(trimethylsilyl)ethyl]oxy}methyl)oxy]phenyl}formamide (90 mg) in EtOAc (8 ml) and EtOH (8 ml) was hydrogenated over 10% palladium on carbon (40 mg) and 20% palladium hydroxide on carbon (20 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent evaporated in vacuo to give the title compound (52 mg). LCMS RT=2.31 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH:13]=[CH:12][C:11]1=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
The solution of 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.00 mmol) in DME (150 mL) and H2O (50 mL), in a pressure flask (500 mL, Chemglass), was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzoic acid (1.97 g, 7.50 mmol) and K2CO3 (4.15 g, 30.0 mmol). The resulting mixture was degassed with Argon for 5 minutes, mixed with Pd(PPh3)4 (0.232 g, 0.20 mmol) and heated with a preheated oil bath (160° C.) under vigorous stirring for 30 minutes. The reaction mixture was filtered through celite, concentrated under vaccum to remove DME. It was then mixed with EtOAc (200 mL) and AcOH (2.5 mL), and shaked. The layers were separated. The organic layer was collected, further washed with brine (70 mL), dried over Na2SO4, filtered, concentrated and purified via a flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) to afford the title compound as a white solid 2.15 g (98%). LC-MS (ES) m/z 440 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3 H), 2.31 (s, 3 H), 6.71 (d, J=9.6 Hz, 1 H), 7.28 (t, J=8.2 Hz, 2 H), 7.57 (d, J=8.4 Hz, 1 H), 7.64 (m, 2 H), 8.00 (d, J=1.6 Hz, 1 H), 8.14 (dd, J1=7.6 Hz, J2=1.6 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O:23][C:24]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)=[O:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][CH:26]([C:24]([OH:25])=[O:23])[CH2:27]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Reactant: COC(=O)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2cc(N3CCC(C(=O)O)C3)nn3ccnc23)nc1OC
Temperature: 180 °C
Yield: 6.4 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1 g, 3.27 mmol), methylpyrrolidine-3-carboxylate (1.69 g, 13.1 mmol), triethylamine (1.32 g, 13.1 mmol) and cesium carbonate (4.26 g, 13.1 mmol) was heated to 180° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxylic acid (80 mg, 6%) as a red solid. LC-MS: 385 [M+1]+, tR=1.258 min
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:8]([O:7][C:5](=[O:6])[C:4]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNCC
Product: CCOC(=O)C(=O)N(CC)CC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.8 %

Procedure:
To 30.00 g (203.2 mmol) diethyloxalate (7) were added at room temperature 42.2 mL diethylamine (406.4 mmol, 2.0 eq). The colorless clear solution was heated to reflux (oil bath temperature: 90° C.) and the reaction was monitored by HPLC. After 2.5 h, the resulting yellow-orange liquid was cooled to room temperature and all volatile compounds (ethanol, diethylamine) were removed in a rotary evaporator (50° C., 10 mbar) furnishing the crude product (35.073 g, 100% by weight) as a yellow liquid. Purification was achieved using a high vacuum distillation (bp 85° C. at 0.08 mbar) furnishing the title compound (30.22 g, 174.4 mmol, 86% by weight) as colorless liquid.