Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=O)[N:17]([CH3:19])[NH:18][C:11]1=2.P(Br)(Br)([Br:23])=O>ClCCl>[Br:23][C:16]1[N:17]([CH3:19])[N:18]=[C:11]2[C:12]=1[CH2:13][CH2:14][CH2:15][N:10]2[C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one (3.16 g) and phosphorus oxybromide (15.5 g) were combined and stirred in a 110° C. oil bath for 4 h. After the reaction mixture had cooled to room temperature, it was dissolved in dichloromethane and added to 200 mL of ice/water. This mixture was stirred vigorously for 30 min. The phases were then separated and the aqueous phase was washed with additional dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 1.16 g of 3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, mp 106-107° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].[Se](=O)=[O:57]>C(O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:57])[CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: CCO
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 70 °C
Yield: 68.5 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (735 mg) in 95% ethanol (10 ml) was added 130 mg of selenium dioxide. The flask was fitted with a water condenser and heated to 70° C. on a mantle. After 45 hours the mixture was cooled to room temperature, filtered through diatomaceous earth and the filtrate poured into a saturated sodium bicarbonate solution. This was extracted with ethyl acetate, and the organic phase was washed with brine and dried over magnesium sulfate. The solution was concentrated and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (514 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[OH-:9].[NH4+]>S(=O)(=O)(O)O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:8])=[O:9])[CH2:3][CH2:2]1
Reactant: N#CC1CCNCC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(2-methyl-phenyl-amino)-1-phenylmethyl)-4-piperidine-carbonitrile (17.89 g) was dissolved in 88 ml conc. sulfuric acid and stirred for 3 d at room temperature. The reaction mixture was poured on ice and adjusted to pH 10 by addition of 30% aqueous ammonium hydroxide and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to yield 4-(2-methyl-phenyl-amino)-1-phenylmethyl)-4-piperidine-carboxamide (10.35 g) as a brown oil. MS: m/z=324 (M+H)+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (1.38 g, 5.07 mmol), 2-chloroisonicotinoyl chloride (1.34 g, 7.6 mmol), DIPEA (1.81 ml, 10.1 mmol) and THF (30 ml) is stirred at room temperature for 12 hours. The mixture is quenched with water (100 ml). The crude product is extracted with EtOAc (2×50 ml), the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (3% MeOH in EtOAc) to afford 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (1.07 g, 51%). 1H NMR (DMSO-d6) δ 10.61 (s, 1H), 8.62 (d, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 7.95 (m, 2 H), 7.59 (d, 2 H), 7.49 (d, 1H), 7.09 (d, 1H), 4.33 (m, 2 H), 3.61 (m, 4 H), 2.92 (m, 2 H), 2.61 (m, 4 H). MS: 412 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].C[O:9][C:10]([C:12]1([CH3:33])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:25])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[NH:13]1)=O>>[Br:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[N:13]3[C:6](=[O:7])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:10](=[O:9])[C:12]3([CH3:33])[CH2:24][C:23]2=1
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Br)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCCCl
Product: CC12Cc3c([nH]c4ccc(Br)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-bromo-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=501.9/503.9
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20](N)[CH:21]=1>C(O)(=O)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:20]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:21]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccccc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 10B (90 mg, 0.517 mmol) and the product from Example 5I (122 mg, 0.569 mmol) in acetic acid (1 mL) was heated at 130° C. for 1 hour. The mixture was then allowed to cool to room temperature, the resulting solid collected and washed with methanol, then dissolved 50 mg of the material in dioxane (2 mL) and added hydrochloric acid followed by removal of the solvent under vacuum to provide the title compound as a hydrochloride salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 2.74 (s, 3H), 7.18 (m, 5H), 7.24 (m, 1H), 7.37 (m, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.80 (s, 1H), 8.99 (d, J=8.5 Hz, 1H), 11.82 (bs, 1H); MS (ESI)+ m/z 359 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:24])[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33]O>C(O)C.CO>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[O:24][N:33]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: NO
Solvent: CCO
Solvent: CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)on3)nc21
Yield: 43.8 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (22 mg, 0.049 mmol) and hydroxylamine (50% aqueous solution, 3.13 μL, 0.051 mmol) in ethanol (1 mL) was heated at reflux for 3 h and LC/MS showed completion of reaction. The reaction mixture was diluted with methanol and purified by preparative HPLC to furnish N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-methylisoxazol-3-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (9 mg, 43.3% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[S:24]([NH:23][C:19]1[C:18]([F:35])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[N:7]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)OC(=O)NCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 88 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.30 g, 0.56 mmol), 1,1-dimethylethyl (2-aminoethyl)carbamate (0.089 g, 0.56 mmol) the title compound of Step A was obtained (0.34 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.13-7.67 (m, 7H), 6.85 (br. s., 1H), 5.80-6.02 (m, 1H), 3.16-3.28 (m, 2H), 2.99-3.13 (m, 2H), 1.40 (s, 9H), 1.37 (s, 9H); m/z (ES+): 663 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Yield: 65 %

Procedure:
A solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (514 mg, 1.4 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 94 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 320 mg (65%) of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ10.45 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.5-7.2 (m, 4H), 7.05 (d, 1H, J=8 Hz), 6.95 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.35 (t, 1H, J=8 Hz), and 5.9 (s, 2H). IR (KBr, cm−1) 3350, 3125, 1628, 1598, and 1583. MS (ES) m/e 351, 353.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1.[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14]>C(O)CC>[ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH:10][C:13]([NH:15][C:16]([NH2:18])=[NH:17])=[NH:14])=[CH:6][CH:5]=1
Reactant: N#CN=C(N)N
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Solvent: CCCO
Product: COc1ccc(CCNC(=N)NC(=N)N)cc1
Yield: 52 %

Procedure:
200 ml of n-propanol was added to 30.0 g (0.16 mol) of 4-methoxyphenethylamine hydrochloride and 14.1 g (0.17 mol) of dicyanodiamide, and the mixture was refluxed for 24 hours, and cooled. The resulting precipitated crystals were filtered off, and the filtrate was concentrated and cooled. The precipitated crystals were recrystallized from n-propanol to obtain 22.6 g of colorless crystals having a melting point of 136 to 139° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20]
Reactant: CN(C)CCN
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Product: CN(C)CCNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl

Procedure:
4-Chloro-5-(2-dimethylaminoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dichloro-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Dimethylaminoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.60 (s, 1H), 5.44 (m, 1H), 5.33 (m, 1H), 3.33 (m, 2H), 2.59 (m, 2H), 2.29 (s, 6H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:32]=[N:31][C:17]3[NH:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[Cl:30])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[CH2:22][N:21]1[CH2:20][CH2:19][NH:18][C:17]2[N:31]=[CH:32][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][C:16]1=2
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(C4=CCNCC4)cc32)c1
Yield: 84 %

Procedure:
4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (105 mg) was dissolved in CH2Cl2/trifluoroacetic acid (3:1, v/v) and stirred at room temperature for two (2) hours. The reaction mixture was concentrated, diluted with CH2Cl2, washed with NaHCO3 (×2), dried, filtered, and concentrated to give the title compound as a pale orange solid (84% yield). M.p. 133-136° C., LCMS: m/z=375.13 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 2.30-2.38 (m, 2H), 3.00-3.06 (m, 1H), 3.28-3.34 (m, 2H), 3.52-3.58 (m, 2H), 4.49 (s, 2H), 5.80 (s, 1H), 6.47 (s, 1H), 6.59 (s, 1H), 7.29 (d, J=2.5 Hz, 1H), 7.37-7.42 (m, 2H), 7.54 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:26])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude benzhydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 500 mL of toluene and the solvent again was removed under vacuum to eliminate excess thionyl chloride, providing crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyoxy) benzyl chloride as a dark oil. NMR (200 MHz, CDCl3): δ0.2 (s,6H); 1.0 (s,9H); 6.0 (s,1H); 6.78 (dd,J1 =1 Hz,J2 =8 Hz,1H); 6.9 (m,2H); 7.2 (t,J=8 Hz,2H); 7.27 and 7.47 (AB q,J=8 Hz,4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2sc(Nc3ccc(Br)cc3)nc2c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3sc(Nc4ccc(Br)cc4)nc3c2)ccn1

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol (1 eq), Potassiumbis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=455
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
3-Chlorobenzaldehyde (15 g, 107 mmol) was added to concentrated sulfuric acid (150 mL) at −20° C., followed by addition of potassium nitrate (11.9 g, 117 mmol) in portions, keeping the temperature below −10° C. After addition, the mixture was stirred for 30 minutes and then poured into ice-water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 5-chloro-2-nitrobenzaldehyde (12.0 g, yield 60.6%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH3:16])[N:9]=2)[S:5][C:6]=1[CH3:7].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:14][C:13]3[C:8]([C:4]4[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=4)=[N:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 9 h
Yield: 22.1 %

Procedure:
2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-ol (200 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (768 mg), 4-dimethylaminopyridine (313 mg), and cesium carbonate (313 mg) were suspended in dimethyl sulfoxide (4 ml), and the mixture was stirred at 130° C. for 9 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (94 mg, yield 22%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[C:41]([F:52])([F:51])[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethyl)phenyl)boronic acid gave 270. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.88 (t, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.77 (dd, J=6.5, 1.5 Hz, 2H), 7.72-7.62 (m, 1H), 7.46 (s, 2H), 4.87 (dd, J=8.5, 3.4 Hz, 1H), 4.82-4.60 (m, 1H), 3.97-3.83 (m, 2H), 3.71 (s, 3H), 3.17 (ddt, J=23.0, 9.2, 2.5 Hz, 1H), 2.15-2.04 (m, 1H), 1.86-1.54 (m, 4H). LCMS (ES+) m/z 499 (M+1).
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])=O)C.Cl.[C:21]([NH2:24])(=[NH:23])[CH3:22].C(O[K])(C)(C)C.Cl>C(O)C.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:23]=[C:21]([CH3:22])[NH:24][C:4](=[O:19])[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCOC
Reactant: CC(=N)N
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCOc1ccccc1-c1cc(=O)[nH]c(C)n1
Yield: 66.6 %

Procedure:
To a solution of 3-[2-(2-methoxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.26 g, 0.98 mmol) in absolute ethanol (10 mL) was added acetamidine hydrochloride (0.3 g, 3.19 mmol) and tBuOK (0.5 g, 4.46 mmol). The reaction mixture refluxed 12 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with CHCl3 (3×20 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with hexane to obtained 0.17 g (67%) 6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-3H-pyrimidin-4-one as a white powder.
Reaction SMILES: OCCNCCN.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.ClC1N=NC(C2C=CC=CC=2)=CC=1C.Cl[C:32]1[N:33]=[N:34][C:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][C:37]=1[CH3:38]>>[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:32]2[N:33]=[N:34][C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:36][C:37]=2[CH3:38])[CH2:10][CH2:9]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(-c2cc(C)c(Cl)nn2)cc1
Agent: Cc1cc(-c2ccccc2)nnc1Cl
Solvent: NCCNCCO
Product: COc1ccc(-c2cc(C)c(NCCN3CCOCC3)nn2)cc1

Procedure:
Operation is carried out as in Example 1, replacing the N-(2-hydroxy ethyl)ethylenediamine by an equivalent quantity of 2-morpholino ethylamine and the 3-chloro 4-methyl 6-phenyl pyridazine by a corresponding quantity of 3-chloro 4-methyl 6-(4-methoxy phenyl)pyridazine.