Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]([CH3:25])([CH3:24])[CH:14](O)[CH2:15][C:16]2[N+:21]([O-:22])=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:24])([CH3:25])/[CH:14]=[CH:15]/[C:16]2[N+:21]([O-:22])=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:26][CH:27]=1)#[N:7]
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccnc[n+]1[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(/C=C/c1ccnc[n+]1[O-])Oc1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
0.23 g of methanesulphonyl chloride was added to a solution of 0.59 g of 6-[3-(4-cyanophenoxy)-2-hydroxy- 3-methylbutyl]pyrimidine 1-oxide and 0.2 g of triethylamine in 10 ml of dichloromethane. The mixture was stirred at 20° C. for 2 hours and then a further 0.46 g of methanesulphonyl chloride and 0.4 g of triethylamine were added. After 2 hours a further 0.6 g of triethylamine was added and the mixture was stirred for 1.5 hours. The mixture was then washed with water and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 0.25 g of (E)-6-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyrimidine 1-oxide in the form of a pale yellow solid of melting point 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: FF
Reactant: Clc1ccnc2ccccc12
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)c2ccccc2n1
Yield: 69.8 %

Procedure:
A solution containing 4-chloroquinoline (1.0 g, 6 mmol), iodine (l.55 g, 6 mmol) and triethylamine (0.60 g, 6 mmol) in CF2ClCFl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution at room temperature using narrow bore PTFE tubing at 20 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (1.01 g). GC/MS analysis showed a 76% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2 fluoro-4-chloroquinoline (0.76 g, 90%); m.p 60°-61° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.78 (CH2CI2); (Found C, 59.7;H, 2.9; N, 7.6. C9H5NClF requires: C, 59.5; H, 2.75; N, 7.7%); δH (400 MHZ, CDCl3, Me4Si) 7.20 ppm (1H, d, JH,3,F 2.4, H-3), 7.62 (1H, d d d, JH5,H6 =JH6,H7 7.4, JH6,H8 1.2, H-6), 7.78 (1H, d d d, JH6,H7 =JH7,H8 7.8, JH5,H7 1.2, H-7), 7.96 (1H, d, JH7,H8 8.4, H-8), 8.19 (1H, d, HH5,H6 8.4, H-5); δF (235 MHz, CDCl3, CFCl3) -61.5 pm (s); δC (100 MHz, CDCl3, Me4Si) 110.2 ppm (d, 2J 45.8, C-3), 124.2 (d, 5J 0.8, C-5), 125.1 (d,4J 2.6, C-4a), 127.0 (d 6J 2.7, C-6), 128.5 (d, 4J 1.5, C-8), 131.6 (s, C-7), 145.9 (d, 3J 18, C-8a), 146.6 (d, 3J 12.5, C-4), 160.2 (d, 1J 242.3, C-2); m/z (E1+) 183 (M+, 26%), 181 (M+, 100%), 146 (35), 126 (15), 75 (12), 50 (11).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]O.C1(C)C=CC=CC=1>C(O)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O.C(OCC)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc(Sc2ccc(OC3CCCC3)cc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ccc(OC2CCCC2)cc1
Reaction time: 18 h
Yield: 96 %

Procedure:
In 100 g of acetic acid was dissolved 13.8 g of 4-cyclopentyloxyphenyl phenyl sulfide obtained in Synthesis Example 1-25. While the solution was maintained at an internal temperature of 30° C., 4.8 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 0.5 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 100 g of toluene, 50 g of ethyl acetate, and 50 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. This was followed by crystallization from hexane, filtration and drying, obtaining 13.5 g of the target compound, 4-cyclopentyloxyphenyl phenyl sulfoxide as white crystals. Yield 96%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:25]3[CH:24]=[N:23][C:32]4[C:27]([CH:26]=3)=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCc1nc2c(N)nc3cc(-c4cnc5ccccc5c4)cnc3c2n1CC(C)(C)O
Yield: 52.1 %

Procedure:
The method described in Example 152 was used to treat 1-(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol (1.0 g, 2.7 mmol) and 3-quinolineboronic acid (0.52 g, 3.0 mmol) in 1-propanol (10 mL) with triphenylphosphine (21.6 mg, 0.0820 mmol), aqueous sodium carbonate (4.1 mL of 2 M), water (2 mL), and palladium (II) acetate (6.2 mg, 0.027 mmol) with the following modifications. The reaction mixture was heated at reflux for four hours. The crude product was purified by recrystallization from ethyl acetate to provide 0.58 g of 1-[4-amino-2-ethyl-7-(quinolin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol as beige needles, mp >270° C.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][N:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccnc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-chloropyridine-4-boronic acid. The title compound was obtained in 10% yield as light yellow foam. MS (m/e): 517.2 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=1[F:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1F
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g) and 2,4-difluoroaniline (2.02 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.6 g), as pale yellow prisms (recrystallized from dichloromethane--n-hexane), m.p. 156°-157.5° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Ge](=O)=O.[OH-].[CH2:17]([N+](CC)(CC)CC)[CH3:18]>C(O)CO>[C:1]1(=[O:12])[O:11][CH2:18][CH2:17][O:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]1=[CH:3][CH:4]=2
Reactant: CC[N+](CC)(CC)CC
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=[Ge]=O
Agent: [OH-]
Solvent: OCCO
Product: O=C1OCCOC(=O)c2ccc1cc2
Reaction time: 4 h

Procedure:
A mixture of 1734 parts by weight of terephthalic acid and 713 parts by weight of ethylene glycol was stirred for 4 hours under 2 atmospheres. Thereafter, 0.3 part by weight of germanium dioxide, 0.3 part by weight of tetraethylammonium hydroxide and 0.4 part by weight of methyl acid phosphate were added, and the reaction was carried out at 260° C. for 2 hours under 1 atmosphere. The reaction product was withdrawn, cooled, pulverized and dried to obtain 1500 parts by weight of an ethylene terephthalate oligomer.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26](B(O)O)=[CH:27][CH:28]=[CH:29][CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Clc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccc3ccc4c(-c5ccccc5-c5ccccc5)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
Next, a mixed solution of 4.9 g of 1-bromo-6-(4-chlorophenyl)pyrene, 3.7 g of 2-biphenylboronic acid, 8.0 g of tripotassium phosphate, 1.2 g of tetrabutylammonium bromide, 84 mg of palladium acetate and 125 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 6 hours. The solution was cooled to room temperature and 100 ml of water was poured into the solution, followed by filtration. The resulting solid was washed with 50 ml of methanol, dissolved in 100 ml of dichloromethane, dried over magnesium sulfate, filtered and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3.6 g of 1-(biphenyl-2-yl)-6-(4-chlorophenyl)pyrene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 600 mg, 1.35 mmol) and (1S*,2R*)-2-phenylcyclohexanol (240 mg, 1.36 mmol) in DMSO (6.0 mL), sodium hydride (63%; 100 mg, 2.63 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (200 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (270 mg, 33%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][C@H:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@@H:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: COc1ccc(CN2C[C@H](C)NC2=O)cc1
Product: COc1ccc(CN2C[C@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Yield: 84.6 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and (S)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 204 and by the reaction and treatment in the same manner as in Example 1, (S)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (180 mg) was obtained. Using the obtained (S)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (180 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (108 mg) was obtained.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12]([O:14][C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]=[C:15]([CH:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]3[CH2:11][C:5]2([CH2:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH:9]3)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NC1CCCCC1
Product: C=CCCC12C=CC(C1)C(C(=O)O)C2C(O)=NC1CCCCC1
Temperature: 135 °C
Yield: 58.2 %

Procedure:
A mixture of 20 g of allylmethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride and 9.09 g of cyclohexylamine is heated at 135° C. for 3 hours, and the product is then distilled in vacuo. 16 g of a yellow, viscous oil distill over between 128° and 138° C. at 2.5 Pa, corresponding to a yield of 58.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([Cl:11])[CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:10][C:6]1[N:5]=[C:4]([Cl:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(Cl)cc(Cl)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(Cl)cc(Cl)nc1CBr
Temperature: 75 °C

Procedure:
A solution of 4,6-dichloro-2-methylnicotinonitrile (2.15 g, 11.50 mmol) in CCl4 (45 ml) was charged with AIBN (1.93 g, 11.75 mmol) and NBS (4.37 g, 24.55 mmol), sealed and heated to 75° C. for 16 hr. The mixture was poured directly onto SiO2 and purified via flash chromatography (5-15% Et2O/hexane) to provide 2-(bromomethyl)-4,6-dichloronicotinonitrile. MS ESI calc'd. for C7H4BrC12N2 [M+H]+ 265. found 265.
Reaction SMILES: [CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][CH:12]=3)[C:8]3[CH:30]=[C:31]([C:35]4[N:39]([CH3:40])[C:38]5[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=5[N:36]=4)[CH:32]=[C:33]([CH3:34])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:8]3[CH:30]=[C:31]([C:35]4[N:39]([CH3:40])[C:38]5[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=5[N:36]=4)[CH:32]=[C:33]([CH3:34])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[CH2:13](N(CC)CC)[CH3:14].Cl.C(N=C=NCCCN(C)C)C.N1(C2C=CN=CC=2)CCCC1.C(O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2,6-dichlorophenyl acetic acid (6.7 g, 0.033 mol) in dichloromethane (170 ml) was added triethylamine (5.9 ml, 0.043 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.1 g, 0.043 mol) and 4-pyrrolidinopyridine (0.58 g, 0.004 mol). Ethanol (2.5 ml, 0.043 mol) was added dropwise and the solution stirred overnight at room temperature. After this time the mixture was washed with water (2×100 ml), 1M HCl (2×100 ml), aq. K2CO3 (sat.; 2×100 ml) and brine (100 ml). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica, using petrol:ether (10:1) as the eluant, to give the ester (7.2 g, 94%) as a colourless oil which solidified on standing at 0° C. 1H NMR (360 MHz, d6 -DMSO) δ 1.26 (3H, t, J=7.1 Hz), 4.01 (2H, s), 4.18 (2H, q, J=7.1 Hz), 7.15 (1H, t, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl.CCN(CC)CC.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>CO.C(Cl)Cl>[CH2:41]([S:43]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[C:2]([F:1])=[C:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:7]1)(=[O:45])=[O:44])[CH3:42]
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCS(=O)(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)CC1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (600 mg, 1.35 mmol, 1.0 equiv) in MeOH (3 mL) was added HCl (4N in dioxane, 3 mL, 12 mmol, 8.9 equiv). After 1 h, the solvent was removed in vacuo. To this residue was added DCM (10 mL) and Et3N (875 μL, 6.28 mmol, 4.65 equiv), and the resulting solution was divided into two equal parts. To the resulting solution was added ethanesulfonyl chloride (90 μL, 0.95 mmol, 1.4 equiv) dropwise by syringe. After 30 min, the reaction was quenched by the addition of aq. satd. NaHCO3. The reaction was diluted with EtOAc, and washed twice with aq. satd. NaHCO3 and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided 1-(3-((4-(ethylsulfonyl)piperazin-1-yl)methyl)-2-fluorophenyl)-3-(2-methylpyridin-4-yl)urea (267 mg, 90%). LCMS m/z (APCI)=436.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:7](F)[CH:8]=2)[N:3]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:28][S:25]([C:21]1[CH:20]=[C:19]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Reactant: Nc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine (0.06 g, 0.00015 mol), (2-aminopyrimidin-5-yl)boronic acid (0.03 g, 0.00023 mol), cesium carbonate (0.097 g, 0.0003 mol), DMF (5 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.005 g, 0.0000075 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and water was added. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 0-5% methanol in chloroform) to provide the desired product (0.05 g, 7%). 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 2H), 8.36 (s, 1H), 8.25 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.21 (s, 2H), 3.85 (s, 8H); 1H NMR (400 MHz, DMSO-d6+D2O): δ 9.12 (s, 2H), 8.20 (s, 1H), 8.14-8.06 (m, 3H), 7.95 (d, J=7.6 Hz, 1H), 7.79 (t, J=7.2 Hz, 2H), 3.83-3.77 (m, 8H), 3.21 (s, 3H). LC-MS (ESI): Calculated mass: 462.1; Observed mass [M+H]+: 463.1 (RT=0.23 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[CH:9])=[N:6][CH:7]=1.CC1C=CC(Br)=NC=1.C[Si](C#C)(C)C.I[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[C:27]([F:34])[C:26]=1[F:35]>[Pd].[Cu]I.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[C:27]([F:34])[C:26]=2[F:35])=[N:6][CH:7]=1
Reactant: CCOc1ccc(I)c(F)c1F
Reactant: C#Cc1ccc(C)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: CCOc1ccc(C#Cc2ccc(C)cn2)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.01 mol of 5-methylpyridin-2-yl-acetylene (which can be prepared from 5-methyl-2-bromopyridine by reaction with trimethylsilyl-acetylene and Pd catalyst and subsequent splitting off of the trimethylsilyl group), 0.01 mol of 4-iodo-2,3-difluorophenetole (for the preparation, see Example 9), 30 ml of triethylamine, 0.2 mmol of Pd catalyst and 0.1 mmol of CuI is stirred at room temperature for 24 hours. The reaction mixture is diluted with petroleum ether and filtered over silica gel. Evaporation and purification give 1-(5methylpyridin-2-yl)-2-(2,3-difluoro-4-ethoxyphenyl) acetylene.