Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CN[C@@H]1CC[C@@H](O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (70 mg, 0.39 mmol) (i.e. the product of Example 28, Step A) and triethylamine (0.082 mL, 0.59 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (181 mg, 0.43 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 3 h, diluted with 5 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 160 mg of the title compounds, compounds of the present invention as a white foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=3)[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Reactant: Fc1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: Fc1ccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.040 g, 0.16 mmol), 4-fluorobenzyl chloride (0.023 ml, 0.19 mmol) and diisopropylethylamine (0.042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloromethane) to yield E4 (0.042 g, 73%) as a solid. C15H16F4N4S requires 360. Found 361 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>ClCCl>[Br:15][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([O:12][CH3:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:14]
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(c1Br)CCC2=O
Yield: 86.4 %

Procedure:
845 mg of 5,7-dimethoxyindan-1-one was dissolved in 40 ml of dichloromethane. Thereafter, 822 mg of N-bromosuccinimide was added to the reaction solution. After completion of the reaction, chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in acetone, and the suspension was filtered, so as to obtain 1.03 g of 4-bromo-5,7-dimethoxyindan-1-one. The obtained product was suspended in a mixed solution consisting of 30 ml of methanol, 10 ml of tetrahydrofuran, and 20 ml of chloroform. Thereafter, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were added to the reaction solution, and the obtained mixture was stirred at room temperature. Approximately 4 hours later, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were further added to the reaction solution. After completion of the reaction, the reaction solution was concentrated. A saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the resultant product, so as to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in t-butyl methyl ether, and the suspension was filtered, so as to obtain 896 mg of the subject compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C@@H:13]4[CH2:14][CH2:15][C@H:10]([C:3]5[C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[NH:1][CH:2]=5)[CH2:11][CH2:12]4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1cc(N2CCN([C@H]3CC[C@@H](c4c[nH]c5ccccc54)CC3)CC2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1H-indol-3-yl)-cyclohexanone (0.53 g, 2.5 mmol), 1-(indol-4-yl)piperazine (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in 1,2-dichloroethane (11 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.52 g (53%) of product as a white solid: mp 85-87° C.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Yield: 99.7 %

Procedure:
To a solution of 4-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (0.5 g, 1.57 mmol) in MeOH (15 mL) was added Pd/C (0.1 g) and the mixture was stirred in hydrogen at 3 atmospheric pressure for 12 h. It was filtered through silica gel pad, washed with MeOH and concentrated to give crude 4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidine (0.5 g, 98% yield) as a grey solid which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 320 (M+1).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.N[C:60]1C=CC=C[CH:61]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:58][C:55]5[CH:56]=[N:57][C:52]([N:49]6[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]6)=[CH:53][CH:54]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:60][CH2:61]1)[CH2:5][O:12][CH2:9]2
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCN(C)CC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazin-1-yl)pyridin-3-amine as the aniline component. (56%, MS=569.5 (M+H))
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[C:12](N(OC)C)=[O:13])=[CH:4][CH:3]=1.[Li]C.[CH3:28]COCC>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[S:10][C:11]=2[C:12](=[O:13])[CH3:28])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide (1.79 g, 4.79 mmol) in THF (97 mL) at −20° C. was added a 1.60 M solution of MeLi in ether (4.19 mL, 6.70 mmol). The reaction was stirred for 30 minutes at −20° C. An additional portion of a 1.60 M solution of MeLi in ether (0.838 mL, 1.34 mmol) was added and the reaction was stirred for 30 more minutes at −20° C. The reaction was quenched by adding saturated ammonium chloride (25 mL) followed by water (35 mL). The mixture was extracted with ethyl acetate (2×150 mL) and the combined organic layers were dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100-40/20) to give 1.27 g (81% yield) of the title compound as a light yellow solid. LC/MS (FA) ES+ 329, 331. 1H NMR (300 MHz, CDCl3) δ: 8.75-8.73 (m, 2H), 7.83-7.81 (m, 2H), 7.34-7.31 (m, 2H). 7.26-7.23 (m, 2H), 4.53 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][N:20]([CH:22]2[CH2:24][CH2:23]2)[CH:21]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:24][CH2:23]3)[CH:21]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Brc1cnn(C2CC2)c1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cnn(C3CC3)c2)cc1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.64 g, 7.3 mmol) and 4-bromo-1-cyclopropyl-1H-pyrazole (1.4 g, 7.3 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 3 hours at ambient temperature in the presence of sodium tert-butylate (3.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (101 mg, 0.146 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is purified by chromatography over silica gel using heptane and ethyl acetate as eluants to yield the expected product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][S:59][CH2:58][CH2:57]2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][S:59][CH2:58][CH2:57]2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCC2CCSCC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCC2CCSCC2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.8 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 78 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(tetrahydro-thiopyran-4-yl)-ethyl]-amine in 1 ml DMF were added. After stirring for 24 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 134 mg (99%) of a yellow solid. MS (ISP) 435.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCOc1ccc(OC)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1ccc(OCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-methyl-2-(4-methoxyphenyloxy)-ethylamine analogously to Example 6.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]O.[C:19]1([CH:25]([CH3:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:26][C:25]([CH3:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:7].[C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:16]
Reactant: Oc1ccccc1
Agent: [O-]O
Solvent: CC(C)=O
Solvent: CC(C)c1ccccc1
Product: CC(=O)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
Phenol is manufactured via air oxidation of cumene to cumene hydroperoxide (CHP), followed by acid-catalyzed cleavage of the latter to phenol and acetone, and known as CHP decomposition. CHP decomposition is a very exothermic reaction which is normally carried out on a commercial scale in continuous stirred or back-mixed reactors. In such reactors only a small fraction of CHP is unreacted at any given time and the reaction medium consists essentially of the products of decomposition of CHP, i.e., phenol and acetone, plus any solvent (e.g., cumene) and other materials added with CHP to the reactor. During cumene oxidation small amounts of dimethyl phenyl carbinol (DMPC) and acetophenone are also formed. In the presence of acid catalyst, DMPC dehydrates to alphamethylstyrene (AMS), a useful by-product. Very high yields of AMS can be obtained from pure DMPC, e.g., 98% yield upon dehydration over acidic silica at 300° C. In the presence of phenol, however, and more specifically in a phenol/acetone/cumene mixture which is a solvent in the decomposition of CHP/DMPC mixtures, the ultimate AMS yield is normally about 50–60 mol % of the DMPC. Main by-products are AMS dimers and cumylphenol which have no commercial value. Formation of cumylphenol also reduces the phenol yield.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([F:43])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=1
Reactant: CN(C[C@@H](N)c1cc(F)cc(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)cc(C(F)(F)F)c1

Procedure:
Compound 35 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.25 (s, 1H), 9.01 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.57 (s, 1H), 3.15 (dd, J=12.3, 8.3 Hz, 1H), 2.95 (dd, J=12.3, 5.5 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH:19]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:30][S:31]([O-:33])=O.[Na+].[Na+].CC(=O)OCC>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:31]([CH3:19])(=[O:33])=[O:30])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Temperature: 20 °C
Reaction time: 12 h
Yield: 39.1 %

Procedure:
To a solution of the title compound of step 2 (4.60 g, 15.93 mmol) in CH2Cl2 (200 mL) was added mCPBA (13.75 g, 79.68 mmol) slowly at 0° C. The mixture was stirred at 20° C. for 12 h and then sat. aq. Na2SO3 (200 mL) was added. EA extractive work up and silica gel chromatography gave the title compound (2.0 g, 39.1% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 7.31-7.27 (m, 1H), 7.10-7.01 (m, 2H), 3.36 (s, 3H). LCMS: 320.8 (M+1)+
Reaction SMILES: C(N(CC)CC)C.O[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1.C1(C)C=CC(S([Cl:32])(=O)=O)=CC=1.C(OCC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:32][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cccc(Oc2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
Triethylamine (2.27 cm3) was added portionwise to a stirred solution of 2-hydroxymethyl-6-phenoxypyridine (3 g), para-toluenesulphonyl chloride (3.7 g), and 4-dimethylaminopyridine (1.17 g) in dichloromethane (30 cm3), whilst the reaction mixture was maintained at the ambient temperature (ca 22° C.) under an atmosphere of nitrogen. After a period of four hours, the reaction mixture was poured into diethyl ether, and washed sequentially with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried, and after removal of the solvent by evaporation under reduced pressure, the crude crude product was subjected to column chromatography on silica gel using dichloromethane as eluent to give 2-chloromethyl-6-phenoxypyridine (2.05 g).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C[O-].[Na+].CO>C(OCC)(=O)C.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:30][C:29]([C:28]3[C:23]([NH2:22])=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:21][N:20]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1cccnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1ncccc1-c1nnc(Cc2ccc(OCc3ccccc3)cc2)[nH]1
Reaction time: 14 h
Yield: 1.1 %

Procedure:
To a methanol (10 mL) solution of 4-benzyloxy-phenylacetic acid hydrazide (200 mg) described in Manufacturing Example 15-1 were added 2-amino-3-cyanopyridine (92 mg) and 28% sodium methoxide-methanol solution (30 mg), which was stirred for 14 hours under heating and reflux. Water and ethyl acetate were added to the reaction solution, and then the organic layer was extracted. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the titled compound (3 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:11]1[N:19]=[CH:18][C:17]2[NH:16][C:15]3[N:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]5)=[CH:26][CH:25]=4)=[CH:23][C:14]=3[C:13]=2[CH:12]=1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:19]=[CH:18][C:17]3[NH:16][C:15]4[N:20]=[CH:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)=[CH:23][C:14]=4[C:13]=3[CH:12]=2)[CH:2]=1
Reactant: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Reactant: OB(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(-c6cccnc6)cc5c4c3)cc2)CC1
Temperature: 140 °C
Yield: 11.2 %

Procedure:
To a mixture of pyridine-2-boronic acid (27 mg, 0.22 mmol), 6-bromo-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (55 mg, 0.11 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9 mg, 0.011 mmol) in acetonitrile (1 mL) and saturated aqueous sodium carbonate solution (1 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM and water and the phases were separated using a hydrophobic fit and the organic phase evaporated. The residue was purified HPLC (C18 column, 50-98% MeCN in water (containing 20 mM triethylamine) over 30 minutes and the fractions containing pure product combined and concentrated then freeze-dried to afford the title compound (6 mg, 11%). 1H NMR (CDCl3 plus CD3OD, 400 MHz): 9.22 (dd, J=2.3, 0.8 Hz, 1H), 9.05 (d, J=1.1 Hz, 1H), 8.86-8.83 (m, 2H), 8.59-8.56 (m, 2H), 8.48-8.44 (m, 1H), 7.73-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.50 (d, J=8.0Hz, 2H), 3.64 (s, 2H), 3.11-3.03 (m, 2H), 2.17-2.04 (m, 3H), 1.93-1.85 (m, 2H), 1.74-1.61 (m, 2H). LCMS (Method A): RT=5.43 min, M+H+=488.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16]>CCOCC>[CH2:1]([O:13][C:19](=[O:20])[NH:18][S:15]([Cl:14])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCO
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A solution of n-dodecyl alcohol (10.7 g, 57.4 mmoles) in 100 mL Et2O was added dropwise to a solution of chlorosulfonyl isocyanate (5.0 mL, 57.4 mmoles) in 100 mL Et2O at ~15° C. under an atmosphere of N2. The resulting mixture was stirred for 2 hours and concentrated in vacuo. The residue was triturated with cold hexanes to give a white solid and collected by filtration to give 19.12 g of a white solid, mp 62°-63° C.