Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[C:33]([OH:38])(=[O:37])[C@H:34]([CH3:36])[OH:35].[C:39]([OH:47])(=[O:46])[C:40]([CH2:42][C:43]([OH:45])=[O:44])=[CH2:41]>O>[C:33]([OH:38])(=[O:37])[CH:34]([CH3:36])[OH:35].[C:39]([OH:47])(=[O:46])[C:40]([CH2:42][C:43]([OH:45])=[O:44])=[CH2:41].[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C[C@H](O)C(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(CC(=O)O)C(=O)O
Solvent: O
Product: CC(O)C(=O)O
Reaction time: 14 h

Procedure:
Polymerisation was performed in the same principle as in Example 9, but the betulin was added to the reaction mixture in three portions during first two hours. The amounts of the ingredients were following: 85.2 g of L-lactic acid (89 mole-%), 7.4 g of itaconic acid (5.5 mole-%), 25 g of betulin (5.5 mole-%) and 0.0375 g of tin(II)octoate. Total polymerisation time was 14 hours. The product was hard, brittle, shiny, orange mass, which was water resistant. Synthesis product was observed to crosslink with end-functionalisation (Example 11) by radicals.
Reaction SMILES: N1C=CC=CC=1.[OH:7][N:8]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:10]#[N:11].[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C(OCC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[C:17]([O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O:7][N:8]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:19])[CH3:18]
Reactant: N#CC(=NO)c1cccs1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
200 mg of 4-dimethylaminopyridine and 6.2 g (0.08 mole) of pyridine are added to a solution of 12 g (0.08 mole) of α-hydroxyiminothien-2-ylacetonitrile (3b) in 75 ml of tetrahydrofuran. With cooling to 0° C., a solution of 18.5 g (0.08 mole) of 4-acetoxybenzenesulfonyl chloride (3a) in 30 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 16 hours at room temperature, and 100 ml of diethyl ether are subsequently added. The precipitated salts are removed by filtration and the solution is concentrated by evaporation. The residual crude product is recrystallised from hexane/ethyl acetate, affording 15 g of crystals with a melting point of 114°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1F.[Cl:18]C1C=CC(C=O)=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[CH:3][CH:2]=[C:7]([Cl:18])[N:6]=2)=[CH:12][CH:13]=1
Reactant: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2cccc(Cl)n2)cc1

Procedure:
To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated, poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (538, 6.5 g, 59%). MS (ESI) [M+H+]+=255.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=O)[CH3:8])=[CH:4][CH:3]=1>[O-]S([O-])(=O)=O.[Cu+2]>[C:2]1([CH3:11])[CH:3]=[CH:4][C:7]([NH:6][C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:1]=1
Reactant: CC(=O)Nc1ccc(C)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: Cc1ccc(Nc2ccc(C)cc2)cc1
Reaction time: 40 h

Procedure:
To a round bottom flask (3 L) equipped with a condenser a Dean-Stark trap, a mechanical stirrer, and an argon-outlet with a thermometer, was added 4'-methylacetanilide (448 g, 3.0 mol), 4-iodotoluene (746 g, 3.4 mol, from Aldrich), potassium carbonate (830 g, 6.0 mol), copper sulfate (20 g), and toluene (50 mL). The reaction mixture was heated at 210° C. for 24 hours in an oil bath. The resulting solution was decanted to a round bottom flask (5 L) and the remaining solid was washed with hot ethanol (3×500). To the combined mixtures were added potassium hydroxide (340 g) and water (400 mL) and then refluxed for 24 h. To resulting solution was added concentrated HCI (400 mL) dropwise followed by toluene (1,000 mL). The mixture was refluxed for 10 min. The hot organic layer (top) was separated, washed with a hot water (500 mL×2), and concentrated under reduced pressure. The resulting solid was recrystallized from the mixture of toluene (100 mL) and hexanes (700 mL). The obtained wet crystals were ground with a mortar and pestle, filtered, washed with hexanes (100 mL), and dried in air for 24 hours to give brown crystals (360 g, 6 mol). The filtrate was concentrated under reduced pressure and recrystallized from the mixture of toluene (20 mL) and hexanes (150 mL) to give a brown solid (120 g, second crop). The combined solid was distilled at 165 oC. and 1 Torr to give a white solid (445 g) while the forerun first portion (15 g, distilled at 65-80°C. and 1 Torr) was discarded. The white solid was recrystallized from hexanes (500 mL) to give a white solid (422 g, 71% yield). Melting point: 80-82° C. (lit. 79°oo C. TCl catalog) 1H-NMR (CDCl3): 7.04 (d, 4H), 6.93 (d, 4H), 5.45 (s, br, 1H), 2.33 (s, 6H) ppm. Note that when iodotoluenes from Oakwood Product Inc., or Charkit Chemical Inc., were used, the above reaction was very slow. Three portions of CuSO4 (50 g) was added every 10 hours and the reaction was completed in 40 hours (over 95% conversion of 4'-methylacetanilide). During work-up after hydrolysis, suction filtraton was required to remove copper residues.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 2-chloro-5-methoxyaniline (23 mg, 0.144 mmol) similar to Example 92 and isolated as a white solid (11 mg, 48%). 1H NMR (CDCl3): 8.84-8.82 (m, 1H), 8.58-8.54 (m, 1H), 7.90-7.85 (m, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.46-7.41 (m, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.01 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:20]([CH:21]=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][CH2:2][CH2:7][CH3:6])=[CH:10][C:11]=1[OH:17])([O:19][CH3:18])=[O:41]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=CC(=O)OC)c(O)c1

Procedure:
A solution of 4-benzyloxy-2-hydroxybenzaldehyde (1.14 g, 5 mmol) and methyl(triphenylphosphoranylidene)acetate (3.51 g, 10 mmol) in THF (40 ml) is stirred at room temperature for 18 hours. The reaction mixture is then concentrated in vacuo and the residue purified by dry column chromatography using 25% EtOAc in hexane to 2:1/hexane:EtOAc. The concentrated residue is triturated with EtOAc/ether to obtain 2-carbomethoxyvinyl-5-butoxyphenol which is confirmed by NMR and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1ccccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1ccccn1
Temperature: 90 °C
Yield: 7.4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.63 mmol), 2-(2-chloroethoxy)pyridine hydrochloride (120 mg, 0.61 mmol) and potassium carbonate (260 mg, 1.9 mmol) in DMF (25 ml) was heated at 90° C. for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)quinazoline (20 mg, 7%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7](C#N)=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[NH:3]1.Br>C(O)(=O)CC>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[NH:3][C:2](=[O:1])[CH:7]=1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]c1=O
Agent: Br
Solvent: CCC(=O)O
Product: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Yield: 136.9 %

Procedure:
The compound was prepared from 2-oxo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carbonitrile (42 g, 126 mmol) and 48% aqueous HBr in propionic acid according to general procedure Ia, step 2 protocol b. Obtained as a white solid (52.98 g, 88%). MS (ISP) 308.3 [(M+H)+]; mp 203-204° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48](O)=O)[CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([CH:39]2[CH2:38][CH2:37][NH:36][CH2:41][CH2:40]2)[CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1cccc(C2CCNCC2)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 25.3 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (80 mg) and 4-(3-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 209, the title compound (25 mg) was obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]#[C:21][C:22]4[CH:23]=[N:24][C:25]([NH2:28])=[N:26][CH:27]=4)[C:14]3=[O:29])[CH:11]=2)[C:6]([CH3:31])([CH3:30])[CH2:5]1)(=O)C.CC(C)([O-])C.[Na+]>CC(O)(C)C.CCOC(C)=O>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:15]2[C:14](=[O:29])[N:13]([C:10]3[CH:11]=[C:12]4[C:7]([C:6]([CH3:31])([CH3:30])[CH2:5][NH:4]4)=[CH:8][CH:9]=3)[CH:18]=[CH:17][C:16]=2[CH3:19])=[CH:27][N:26]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(-n3ccc(C)c(C#Cc4cnc(N)nc4)c3=O)cc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1ccn(-c2ccc3c(c2)NCC3(C)C)c(=O)c1C#Cc1cnc(N)nc1
Temperature: 100 °C

Procedure:
A mixture of 1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-2(1H)-pyridinone (0.103 g, 0.25 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in tBuOH (4 mL) was heated under microwave radiation at 100° C. for 10 min. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl and brine. The solids formed were filtered and recombined with the organic fraction. After concentrating the organic fraction in vacuo, the residue was purified by silica gel chromatography using 0-10% MeOH in EtOAc to afford 3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-4-methyl-2(1H)-pyridinone as a light yellow solid. Found M+H+=372.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([C:72]([C:78]([OH:80])=[O:79])([CH2:74][CH2:75][CH2:76][CH3:77])[NH2:73])[CH2:69][CH2:70][CH3:71]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:73][C:72]([CH2:74][CH2:75][CH2:76][CH3:77])([C:78]([OH:80])=[O:79])[CH2:68][CH2:69][CH2:70][CH3:71])=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CCCCC(N)(CCCC)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCC(CCCC)(NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 34.3 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.020 g, 0.037 mmol) and NMM (0.040 ml, 0.363 mmol) were dissolved in DCM (5 ml) at 30° C. TBTU (a total of 0.016 g, 0.050 mmol) were added in portions and the mixture was stirred for 1 h. 2-Butylnorleucine (0.007 g, 0.037 mmol) was added and the mixture was stirred at 30° C. for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.009 g (34% yield) of the title product was obtained as a white solid. M/z: 710.1. 1H NMR (DMSO, 400 MHz): δ 0.73-0.82 (m, 6H), 0.88-1.22 (m, 8H), 1.56-1.69 (m, 2H), 1.96-2.07 (m, 2H), 3.71 (d, 2H), 4.32 (d, 1H), 4.36 (ABq, 2H), 4.52 (s, 2H), 5.16 (d, 1H), 6.95-7.01 (m, 2H), 7.11-7.26 (m, 4H), 7.30-7.40 (m, 4H), 7.61 (s, 1H), 7.98-8.06 (m, 2H), 8.25-8.42 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]1[O:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1)C1C=CC=CC=1.C[Si](I)(C)C.N#N.CO>C(#N)C.O>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]1[O:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1
Reactant: Cc1cccc(-c2nnc(-c3nc4ccc(C)cn4c(=O)c3OCc3ccccc3)o2)c1
Agent: C[Si](C)(C)I
Agent: N#N
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Cc1cccc(-c2nnc(-c3nc4ccc(C)cn4c(=O)c3O)o2)c1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of the product from Example 8.4 (20 mg, 0.047 mmol) in acetonitrile (5 mL), was added trimethylsilyl iodide (54 uL, 0.38 mmol) dropwise under N2 at room temperature. After 2 h, methanol (5 mL) was added and the solution was stirred for 10 min. Water (10 mL) was added and the reaction extracted with dichloromethane. The organic phase was washed with aqueous sodium bisulfite solution, dried (Na2SO4) and concentrated in vacuo to afford the desired compound (88.6%).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH:9](P(=O)([O-])[O-])[F:10])=[C:5](CC)[C:4]=1[Br:17])C.[Li+].CC([N-]C(C)C)C.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.O>C1COCC1>[Br:17][C:4]1[CH:5]=[C:6](/[C:9](/[F:10])=[CH:26]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCc1ccc(C(F)P(=O)([O-])[O-])c(CC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A solution of diethyl(3-bromophenyl)fluoromethylphosphonate (2.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature methyl 4-formylbenzoate (1.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (Z)-methyl 4-(2-(3-bromophenyl)-2-fluorovinyl)benzoate (0.73 g, 33.6%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1>COCCO>[CH2:1]([NH:4][C:5]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN=C=O
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: COCCO
Product: CCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
Propyl isocyanate (2.38 g) was added dropwise to 5.13 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of 2-methoxyethanol. The mixture was stirred at room temperature for 10 minutes. Crystals precipitated were collected by filtration and recrystallized from methanol-acetonitrile to obtain 4.91 g of 2-(propylcarbamoyl)amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][OH:21])=[CH:6]\[C:7]([O:9]CC)=O.C[Si]([N:27]=[C:28]=[S:29])(C)C.O>O1CCCC1>[OH:21][CH2:20][CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[N:4]([CH2:3][C:2]([NH2:1])=[O:22])[C:28](=[S:29])[NH:27][C:7](=[O:9])[CH:6]=1
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1ccccc1OCCO
Reactant: C[Si](C)(C)N=C=S
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccccc2OCCO)cc(=O)[nH]c1=S
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
To a solution of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(2-(2-hydroxyethoxy)phenyl)acrylate (1.0 g, 3.25 mmol) in tetrahydrofuran (15 mL) was added trimethylsilyl isothiocyanate (1.7 g, 12.9 mmol), and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into a flask containing water and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid, which was purified by flash chromatography (2-5% MeOH:CH2Cl2) to give the title compound (330 mg, 31.7%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][C:28]=3F)=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:32]3[C:27](=[CH:28][CH:29]=[N:30][CH:31]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccncc2F)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cnccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dissolve (3-{[3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester (0.65 g, 0.0014 mol) in N,N-dimethylformamide (6 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.35 mL, 0.0017 mol) and stir for 15 min. at ambient temperature. Quench the dark mixture with water and follow with the addition of solid sodium chloride. Extract with ethyl acetate and wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane allowing for the isolation of 0.44 g (71%) of the desired product as an off white solid. MS(S): (M+1)+ 447.2, 448.2 m/z.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])[S:6][C:5]=1[C:13]([OH:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][Si:9]([CH3:10])([CH3:11])[C:7]1[S:6][C:5]2[C:13](=[O:14])[O:15][CH2:2][CH2:3][C:4]=2[CH:8]=1
Reactant: C[Si](C)(C)c1cc(CCO)c(C(=O)O)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cc2c(s1)C(=O)OCC2
Temperature: 10 °C

Procedure:
A mixture of 3-(2-Hydroxy-ethyl)-5-trimethylsilanyl-thiophene-2-carboxylic acid (4.1 g) and p-Toluenesulfonic acid (577.9 mg) in toluene (100 mL) was heated to 10° C. for 6 h. The solvent was removed in vacuum and the residue taken up in water and ethyl acetate. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 226.37 (C10H14O2SSi); MS (ESI): 227 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)O1.COC1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>>[N:26]1([C:23]2[N:24]=[CH:25][C:20]([C:2]3[S:3][C:4]4[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=4[N:6]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Oc1ccc2nc(Br)sc2c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Product: Oc1ccc2nc(-c3ccc(N4CCOCC4)nc3)sc2c1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
2-Bromo-1,3-benzothiazol-6-ol (40 mg, 0.17 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (61 mg, 0.21 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine The reaction mixture was cooled to rt and concentrated. Flash chromatography (Heptane/EtOAc 1:1) gave the title compound (21 mg) as an off-white solid. 1H NMR δ 9.80 (br s, 1 H) 8.71 (d, 1 H) 8.09 (dd, 1 H) 7.77 (d, 1 H) 7.37 (d, 1 H) 6.98-6.93 (m, 2 H) 3.73-3.69 (m, 4 H) 3.61-3.56 (m, 4 H); MS ink (M+H) 314.