Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c2c1OCO2
Temperature: 110 °C

Procedure:
3-Bromo-6-methoxycatechol (23.4 g) was dissolved in DMF (150 ml), and dibromomethane (15.4 ml) and potassium fluoride (31.1 g) were added thereto, followed by heating at 110° C. for 6 hours with stirring. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with an aqueous solution of sodium hydroxide, with water, and with a saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to give Compound IIbj-a (5.6 g, 40%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 62.9 %

Procedure:
Example 58 was prepared in an analogous manner to Example 43 from Intermediate 14 (0.12 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.057 g).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[NH:28][CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1.C=O.C(O)(=O)C>ClCCl>[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[N:28]([CH3:1])[CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5C(CCN5C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
Sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 442F, 29 mg, 0.049 mmol), paraformaldehyde (14.63 mg, 0.487 mmol) and acetic acid (5.58 μl, 0.097 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 5 hours. More paraformaldehyde (14.63 mg, 0.487 mmol) and sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) were added and stirring continued overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-30% ethyl acetate/hexanes). 2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:19]=[C:17]([CH2:16][Cl:15])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(CCl)cs1
Yield: 23.4 %

Procedure:
A solution of N-(2-t-butyloxycarbonylaminoethyl)thiourea (1.00 g, 4.54 mol) in ethanol (22 mL) was added 1,3-dichloroacetone (2.60 g, 20.47 mmol) at room temperature. After 2 hours the reaction mixture was concentrated under reduced pressure. The residue was triturated with ether and filtered to afford the solid precipitate of title product (1.40 g), which was used for next step without further purification. 1H NMR (CDCl3) δ 1.40 (s, 9H), 3.35 (m, 4H), 4.38 (s, 2H), 5.00 (br s, 1H), 6.40 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][CH3:22])=[C:10]([CH2:19]O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.S(Cl)(Cl)=O>[N:23]([CH2:19][C:10]1[C:9]([CH2:21][CH3:22])=[N:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[C:11]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 218.1 %

Procedure:
To [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (24.9 g, 82 mmol) was added thionyl chloride (90 mL, 1.23 mmol) and the mixture was heated to 80° C. under an atmosphere of nitrogen. After 2 h the mixture was cooled, evaporated and the residue azeotroped with toluene. The residue was then dissolved in a solution of sodium azide (7.98 g, 123 mmol) in DMSO (120 mL). The mixture was stirred for 16 h. The above procedure was repeated on the same scale and the 2 reactions combined for work-up. The combined DMSO mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was extracted thoroughly with ethyl acetate and the combined organics were washed with water, then brine, dried and evaporated to afford 58.9 g of a brown solid. The product was purified by flash chomatography on 1.5 kg of silica using a step gradient from 3:1 to 2:1 cyclohexane/ethyl acetate to afford 39.94 g of the title compound. LC-MS m/z 330 (M+H)+, 2.21 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].[C:24](OC(=O)C)(=[O:26])[CH3:25].S(=O)(=O)(O)O>>[C:24]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(N)s2)ccn1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(NC(C)=O)s2)ccn1
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a stirred solution of N-{4-[5-amino-4-(2-chlorophenyl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.020 g, 0.058 mmol) in anhydrous acetic anhydride (1.00 mL, 10.60 mmol) was added dropwise concentrated sulfuric acid (0.002 mL, 0.030 mmol) and stirred for 18 h. The reaction was quenched by the dropwise addition of a triethylamine (0.200 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexanes) to provide 0.014 g of product as a yellow oil (62%). LC/MS (AA) ES+ 387, 389. 1H NMR (400 MHz, d1 CDCl3) δ: 9.10 (br s, 1H), 8.63 (br s, 1H), 8.31-8.30 (m, 0.5H), 7.64-7.24 (m, 6.5H), 2.18 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].[CH2:15]([SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:15]([S:27][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCS
Reactant: C/C=C/C(=O)C1C(C)C=CCC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-damascone (10.0 g; 52.1 mmol) and 1-dodecanthiol (8.42 g, 41.7 mmol) in THF (150 ml) was treated with DBU (7.92 g; 52.1 mmol) and stirred at 45° C. for 90 min. The reaction solution was treated with 5% aqueous HCl, extracted twice with ether, washed with H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated at 70° C./0.01 mbar. Yield of crude product: 16.2 g (99%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CN(C)CCN(C)C.CCCCCC.CN(C)[CH:34]=[O:35].[NH4+].[Cl-]>CCOCC>[CH:34]([CH:7]1[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:6]1)=[O:35]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
tert-butyl 8-azaspiro[4.5]decane-8-carboxylate (Intermediate 71, 6 g, 25.07 mmol) dissolved in 150 ml of Et2O was cooled to −78° C., then N,N,N′,N′-tetramethyl ethylendiamine (9.08 ml, 60.16 mmol) and secBuLi 1.4M in hexane (42.95 ml, 60.16 mmol) were added. After 10 minutes at −60° C., the temperature was raised to −20° C. for 60 minutes, then the reaction was cooled to −78° C. and dimethylformamide (4.47 ml, 60.16 mmol, dissolved in 5 ml of Et2O) was added. After 30 minutes a saturated aqueous solution of NH4Cl (30 ml) was slowly added, then reaction was allowed to reach room temperature. Reaction was extracted with Et2O (3×100 ml), the organic solvent was dried (Na2SO4) and evaporated to obtain 4 g of the title compound as yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2snnc2c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccc2snnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Benzo[1,2,3]thiadiazole-5-carboxylic acid (2.70 g, 15.0 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to 0° C. To this was added triethylamine (2.50 mL, 18.0 mmol) followed by isobutylchloroformate (2.15 mL, 16.5 mmol) in a dropwise manner. The resulting slurry was stirred for a further 30 minutes at 0° C. and then filtered into a mixture of sodium borohydride (1.14 g, 30 mmol) in ice water (20 mL). The resulting mixture was stirred at 0° C. for 15 minutes, evaporated to one quarter of its volume and then partitioned between a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and ethyl acetate (3×50 mL). The organic phases were combined and then dried over sodium sulfate. This was followed by concentration under reduced pressure to provide an oil which was purified by column chromatography on silica gel using an ethyl acetate and hexane solvent system. This provided the desired product as a yellow solid (1.40 g, 56%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:14]2[CH:15]=[C:11]([C:9]([C:6]3[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=3)=[O:10])[N:12]([CH3:16])[CH:13]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cn1cccc1C(=O)c1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)c1ccc(Cl)nc1

Procedure:
Following the protocol of Example 8 and employing (6-chloropyridin-3-yl)-(1-methyl-1H-pyrrol-2-yl)methanone hydrochloride in place of (1-methyl-1H-pyrrol-2-yl)-pyridin-3-ylmethanone hydrochloride and 4-chlorobenzoyl chloride in place of 4-fluorobenzoyl chloride, the title compound was obtained and recrystallized from MTBE: mp 150-152° C. ES-MS m/z=360 (M++H). 1H NMR (300 MHz, CDCl3) δ 4.1 (s, 3H); 7.2 (s, 1H); 7.5 (m, 3H); 7.56 (s, 1H); 7.8 (dd, 2H); 8.05 (d, 1H); 8.8 (s, 1H). Anal calc'd for C18H12C2N2O2: 60.19; H, 3.37; N, 7.8. Found: C, 59.9; H, 3.34; N, 7.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:12][C:10]2[S:11][C:7]3[C:6]([C:13]4[NH:14][N:15]=[N:16][N:17]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2nnn[nH]2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2nnn[nH]2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 4-methoxy-7-(1H-tetrazol-5-yl)-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride in pyridine the title compound was obtained as a tan solid (70% yield), MS: m/e=371.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([C:33](O)=[O:34])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH2:4][CH:3]([CH3:17])[CH2:2][NH:1][C:33]([C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:34])(=[O:8])=[O:7])=[CH:14][CH:13]=1)#[N:16]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: CC(CN)CNS(=O)(=O)c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNS(=O)(=O)c3ccc(C#N)cc3)ccc21
Yield: 65.4 %

Procedure:
A solution of the compound obtained in Step 2 (65.7 mg, 0.26 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (62.1 mg, 0.26 mmol), HATU (128 mg, 0.34 mmol) and TEA (0.108 mL, 0.78 mmol) in DMF (1.25 mL) was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give the title compound (81 mg, 0.170 mmol, 65.7%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CC[C@@H](C(=O)O)c1ccccc1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 41 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (R)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.06 g, 36%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][N:54]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.4 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (60.8 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-(+)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring at room temperature for 7 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (18.3 mg). This was purified again by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (12.3 mg, 23.8%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:19]=[N:20][CH:21]=[N:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]([CH:25]=[CH2:26])(O)[C:6]=2[CH:5]=1.[NH2:27][C:28]([NH2:30])=[S:29]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)=[CH:11][CH:12]=3)[C:7]3([CH2:25][CH2:26][S:29][C:28]([NH2:30])=[N:27]3)[C:6]=2[CH:5]=1
Reactant: NC(N)=S
Reactant: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C1(CCSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 pt, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Cl-].[NH4+].COCCOC.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:32][CH3:33])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1>O.[Zn]>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:32][CH3:33])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)(=[O:17])=[O:18])[CH:15]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(N)cc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A 27% solution of ammonium chloride in water (35.00 mL) was mixed with 1,2-dimethoxyethane (21.00 mL) and the mixture cooled to 15° C. 1-(5-Chloro-2-methoxy-benzenesulfonyl)-7-nitro-1,2,3,4-tetrahydro-quinoline (1.00 g, 26.10 mmol) was added under vigorous stirring, followed by zinc powder (2.22 g, 33.96 mmol). The mixture was warmed to room temperature and stirred for 1 hour. After filtering off the solids, the organic solvent was evaporated and the residual slurry extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylamine as a brown solid, 0.32 g (35%), MS (ISP): m/e=353.2 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:12]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:26]>C1COCC1>[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)=[O:35])=[CH:20][CH:19]=2)[CH:12]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 N solution of HCl in dioxane (1.2 mL, 4.96 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (50 mg, 0.156 mmol) in CH2Cl2 (0.67 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 4 h and concentrated in vacuo to afford 50.9 mg of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. DIEA (80 μL, 0.454 mmol, 2 equiv) is added to a suspension of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine (50 mg, 0.227 mmol) in THF (0.4 mL), under an argon atmosphere. 4-Ethyl-phenyl-isocyanate (40 μL, 0.250 mmol, 1.1 equiv) is then added. The resulting yellow solution is stirred at rt for 2 h and concentrated in vacuo. The residue is purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 98/2). A second purification affords the title compound as a white solid: ES-MS: 367.0 [M+H]+; single peak at tR=8.94 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 95/5).