Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 82 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 (with conversion to the HCl salt as outlined for Example 2), this product was prepared in 82% yield from 6-chloro-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. of free-base: 140°-141° C.; For HCl salt: M.P. 232°-233° C.; LC-MS: 312 (MH+); anal. RP18-HPLC RT: 5.68 min.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[ClH:10].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][Cl:16])[CH3:12].[OH-].[Na+]>O>[ClH:16].[ClH:10].[ClH:16].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH3:12]
Reactant: OCCN1CCNCC1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCN1CCN(CCO)CC1
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 76.0 g (0.58 mol) of 1-(2-hydroxyethyl)piperazine in 200 ml of water was added dropwise 201.0 g (0.58 mol) of a 50% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride. The pH was maintained at 10 by addition of 25% NaOH while the solution was stirred for 18 hours. Water was removed to give a thick oil which was extracted with ethanol. The ethanolic solution was filtered, then the ethanol was removed. The resulting liquid was distilled to give 67.7 g (51%) (b.p. 110-112° C./0.1 Torr) of the alcohol as a light brown liquid. The trihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].BrC[CH2:27][CH2:28][O:29][CH2:30][CH2:31]CBr>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCOCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: CCOCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 2-bromomethyl-ethyl ether, the title product was prepared in the same manner as described for example 1a (83%). Pink, viscous oil. MS: m/e=397(M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) (0.23 g, 1.18 mmol, 1 eq) was dissolved in dichloromethane and DIPEA (2.5 eq), under nitrogen, and 2-chlorobenzoic acid chloride (0.15 ml, 1.18 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 3:1) and the desired product (R)-methyl 1-(2-chlorobenzamido)-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate (B-28) was thus obtained. Yield: 83%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[F:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:3]2[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=[C:2]2[CH3:1])=[C:12]([F:19])[CH:13]=1)#[N:16]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)O)cn1-c1ccc(C#N)cc1F
Temperature: 100 °C

Procedure:
A mixture of 2-methyl-1H-imidazole-4-carboxylic acid (400 mg), 4-fluoro-3-fluorobenzonitrile (0.53 g), and K2CO3 (1.3 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. for 30 minutes in a microwave. The crude product is purified by HPLC. LC (method 20): tR=1.24 min; Mass spectrum (APCI): m/z=246 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[F:25][C:2]([F:1])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1cnc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)cn1
Reaction time: 8 h

Procedure:
To the intermediate of Example 181 Step A (100 mg, 0.3 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.8 mL). The reaction was allowed to proceed overnight then concentrated neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step A that was used without further purification.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:21]4[C:25]5=[N:26][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=6)=[CH:28][N:29]=[C:24]5[N:23]=[N:22]4)[CH2:15]3)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[CH3:35][N:33]1[CH:34]=[C:30]([C:27]2[N:26]=[C:25]3[N:21]([CH2:20][CH:16]4[CH2:17][CH2:18][CH2:19][N:14]([C:11]5[N:12]=[CH:13][C:8]([C:5]6[CH2:6][CH2:7][NH:2][CH2:3][CH:4]=6)=[CH:9][N:10]=5)[CH2:15]4)[N:22]=[N:23][C:24]3=[N:29][CH:28]=2)[CH:31]=[N:32]1
Reactant: CN1CC=C(c2cnc(N3CCCC(Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCNCC6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Yield: 82 %

Procedure:
1-((1-(5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (125 mg, 0.22 mmol) was dissolved in CH2Cl2 (5 ml), and then 4 N HCl dissolved in dioxane (1 ml) was added, followed by stirring at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then purified with ether, to give 6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (90 mg, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([C:30]2[NH:21][C:20]3[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: COc1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(N(C)C)cc4)nc3c2)cc1

Procedure:
Compound 208 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-methoxybenzoyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.08 (d, J=9.5 Hz, 2H), 8.01 (d, J=7 Hz, 2H), 7.79 (dd, J=2, 9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.09 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 3.82 (s, 3H), 3.08 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40].C(N(CC)CC)C>>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)N(C)C)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.076 mmol), dimethylcarbamoyl chloride (41 mg, 0.379 mmol) and triethylamine (38 mg, 0.379 mmol) was stirred 0.5 h. Then the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([I:22])=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([I:22])=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: COCCOCCl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)[nH]2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reaction time: 18 h

Procedure:
To a mixture of 1-(7-iodo-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.65 g, 4.02 mmol) and THF (20 mL) was added DIPEA (2.10 mL, 12.1 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.01 mL, 8.85 mmol) at 23° C. After stirring for 18 h, the reaction mixture was concentrated under reduced pressure. The residue was used in subsequent reactions without further purification (1.89 g, 94%). MS (ESI): mass calcd. for C18H19IN4O5, 498.0; m/z found, 499.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.85 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H), 8.17 (d, J=1.4 Hz, 1H), 8.00 (dd, J=8.3, 1.6 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 5.65 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.50-3.48 (m, 2H), 3.26-3.23 (m, 2H), 3.05 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Reactant: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Yield: 80.7 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (154 mg, 0.62 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) (153 mg, 0.31 mmol) and the obtained residue was purified by Purif silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (181 mg, 81%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:28][OH:29])[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>CO>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([CH2:28][OH:29])[CH2:26][CH2:25][C:24](=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=C1CCC(CO)(c2ccc(Br)cc2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=C1CCC(CO)(c2ccc(Br)cc2)CC1
Yield: 86.3 %

Procedure:
To a round bottom flask containing methanol (60 ml) was added sodium hydride (0.78 g, 19.37 mmol) portion-wise at room temperature under stirring, Trimethyl phosphonoacetate (2.58 ml, 17.88 mmol) was added drop-wise and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was then added 4-(4-bromophenyl)-4-(hydroxymethyl)cyclohexanone (4.22 g, 14.90 mmol) in several portions and stirred at room temperature for overnight. The reaction mixture was then quenched with a saturated solution of ammonium chloride and subsequently concentrated to remove excess methanol. The residue was taken in saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic portion was dried over sodium sulfate and concentrated to afford a crude product. Column purification afforded the title compound as viscous oil (4.36 g, 86% yield). LC/MS, ESI-MS: non-ionizable, RT: 1.32 (Condition E).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:16]=[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:11]1([CH2:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]3=[O:16])[CH:9]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C1CCCCN1c1ccccc1O
Reactant: N#Cc1ccc(Cn2ccnc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1Oc1ccccc1N1CCCCC1=O
Temperature: 50 °C

Procedure:
2-Fluoro-4-imidazol-1-ylmethyl-benzonitrile (as described in Step E above) (0.080 g, 0.4 mmol), 2-(2-oxo-piperidin-1-yl)-phenol (as described in Step F above) (0.091 g, 0.5 mmol) and cesium carbonate (0.261 g, 0.8 mmol) were combined in DMF (2.0 mL) and heated at 50° C. for 18 hr. The reaction mixture was partitioned between EtOAc and a minimum volume of H2O. Additional product was salted out from the aqueous layer with solid NaCl, and extracted into EtOAc. The organic layers were combined, dried (Na2SO4), filtered and concentrated to give the title compound after RP HPLC on a Waters Prep Pak column eluting with a 0.1% TFA/H2O: 0.1% TFA/CH3CN gradient followed by conversion to the free base.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:20]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[NH2:25][OH:26]>C(Cl)Cl>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:22])[NH:25][OH:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reactant: NO
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)phenyl isocyanate (16.5 g) was dissolved in 100 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 17.7 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 17.7 g of the product and 12.5 g of dimethyl sulfate were dissolved in 200 ml of toluene, and after addition of 0.16 g of tetra-n-butylammonium bromide to the mixture, 11 ml of 10 N sodium hydroxide were dropwise added thereto at 20°-22° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-200 mesh; eluting solvent, tetrahydrofuran-benzene (1:3) mixture) to obtain 16.2 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. The product was confirmed to be the same product as obtained in Example 1 by IR, NMR, TLC and melting point.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:24]([C:23]1[S:22][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[C:5]=2[N:21]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Product: CCCCCc1nc2c(N3CCNCC3)nc(N)nc2s1
Yield: 67 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using hexanoyl chloride, yielding the title compound in 67% yield.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[O:6]1[C:10]2C=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl.CCOCC>[O:2]1[C:3]2[CH:7]=[CH:8][C:9]([CH:10]=[O:6])=[CH:14][C:13]=2[CH2:12][CH2:1]1
Reactant: COC(Cl)Cl
Reactant: c1ccc2c(c1)CCO2
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a stirred solution of α,α-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40° C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2Cl2 (5 mL) maintaining the temperature at or below -35° C. The mixture was warmed to 0° C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119°-121° C. at 0.3 mm Hg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.N1[CH:27]=[C:26]([C:28]2[S:32][C:31]([O:33][C@@H:34]3[CH:41]4[CH2:42][N:37]5[CH2:38][CH:39]([CH2:43][CH:35]3[CH2:36]5)[CH2:40]4)=[N:30]C=2)[CH:25]=N1.[NH3:44]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:26]([C:28]1[S:32][C:31]([O:33][C@@H:34]2[CH:41]3[CH2:42][N:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)=[N:30][N:44]=1)([CH3:25])([CH3:12])[CH3:27]
Reactant: N
Reactant: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1nnc(OC2C3CC4CC2CN(C4)C3)s1

Procedure:
The free base of the title compound was prepared from the product of Example 56A (929 mg, 3.02 mmol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.42 (s, 9H) 1.99 (d, J=13.6 Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H). MS (DCI/NH3) m/z=294 (M+H)+. Anal. Calcd. for C15H23N3OS.C7H8O3S: C, 56.75; H, 6.71; N, 9.02. Found: C, 56.62; H, 6.81; N, 8.98.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[Cl:11][CH2:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of ortho-nitrophenol (5.0 g, 35.8 mmoles) and 2-chloroethanol (9.5 ml, 143 mmoles) in THF (50 mL), in a round bottom flask, under nitrogen, was stirred at room temperature. Triphenylphosphine (14 g, 53.7 mmoles) was added, followed by diethylazodicarboxylate dropwise (8.5 mL, 53.7 mmoles). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water (1×), brine (1×), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 40% EtOAc/hexane to give the title compound as an off-white solid (5.6 g, 28 mmoles).
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].Cl[CH2:18][C:19](=[O:31])[CH2:20][C:21]1[C:22]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=2[S:24][CH:25]=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:18][C:19](=[O:31])[CH2:20][C:21]1[C:22]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=2[S:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1csc2ccc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1csc2ccc(Cl)cc12
Yield: 57 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(5-chlorobenzo[b]thiophen-3-yl)-propan-2-one (4.43 g, 17.1 mmol) with acetic acid (2.0 mL, 2.1 g, 35 mmol) and triethylamine (4.9 mL, 3.6 g, 35 mmol). Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product, a pale yellow solid (2.76 g, 57% yield): 1H NMR (400 MHz, CDCl3) δ2.16 (s, 3H) 3.94 (d, J=1.0 Hz, 2H) 4.73 (s, 2H) 7.34 (ddd, J=8.6, 2.0, 0.5 Hz, 1H) 7.39-7.42 (m, 1H) 7.65 (d, J=2.0 Hz, 1H) 7.78 (dd, J=8.6, 0.5 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>C1C=CC=CC=1.CO>[CH3:17][C:3]1([CH:1]=[N:19][CH3:18])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: Cn1c2c(c3ccccc31)C(C)(C=O)CCS2
Reactant: CN
Solvent: c1ccccc1
Solvent: CO
Product: CN=CC1(C)CCSc2c1c1ccccc1n2C
Reaction time: 2 h

Procedure:
To a solution of the product (2.0 g) of the above (1) in benzene (20 ml) is added a 30% solution (14 ml) of methylamine in methanol. The solution is stirred for 2 hours and evaporated to give 4,9-dimethyl-4-methyliminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (IR: νmaxCHCl3 1660 cm-1). The product is dissolved in methanol (20 ml) and sodium borohydride (930 mg) is added thereto on ice bath. The mixture is stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The ethereal extract is again extracted with hydrochloric acid. The extract is made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The extract is washed with a saline solution, dried and evaporated to give an oil. Crystallization from hydrochloric acid--ethanol gives the hydrochloride (2.06 g) of the title compound melting at 274° C. (decomp.). Yield: 86%.