Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([O:15]C(C)(C)C)=O)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][NH:32][CH3:33].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:33][N:32]([CH2:31][C:23]1[N:22]([CH3:21])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH2:4][C:3](=[O:20])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1)=[O:15]
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2NCC1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN1Cc2cc(C(=O)N(C)Cc3cc4ccccc4n3C)ccc2NCC1=O
Yield: 91.8 %

Procedure:
According to the procedure of Example 8, except using tert-butyl 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.60 g, 2.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.35 g, 2.2 mmole), Et3N (0.62 mL, 4,4 mmole), HOBt.H2O (0.30 g, 2.2 mmole), and EDC.HCl (0.42 g, 2.2 mmole), the title compound (0.76 g, 92%) was prepared as an off-white solid following flash chromatography on silica gel (5% MeOH/CHCl3): MS (ES) m/e 377.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.CS(O[CH2:30][C@@H:31]1[O:35][C:34](=[O:36])[N:33]([C:37]2[CH:38]=[CH:39][C:40]3[S:41][CH2:42][C:43](=[O:47])[NH:44][C:45]=3[N:46]=2)[CH2:32]1)(=O)=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:30][C@H:31]5[O:35][C:34](=[O:36])[N:33]([C:37]6[CH:38]=[CH:39][C:40]7[S:41][CH2:42][C:43](=[O:47])[NH:44][C:45]=7[N:46]=6)[CH2:32]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Product: O=C1CSc2ccc(N3C[C@@H](CN4CCN(c5cc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)CC4)OC3=O)nc2N1

Procedure:
In analogy to Example 1, starting from 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (commercial; 166 mg) and 6-[(5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-b]-1,4-thiazin-3(4H)-one (prepared in analogy to its (S) enantiomer described in WO 2010/041194; 180 mg), the title compound was obtained as a beige solid after CC (DCM/MeOH 9:1) and crystallization from EtOH.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H].[ClH:19]>CO.[Pd]>[ClH:19].[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1
Yield: 57 %

Procedure:
A solution of (4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[F:27][C:28]1[CH:29]=[C:30]2[C:35](=O)[O:34][C:32](=[O:33])[C:31]2=[CH:37][CH:38]=1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][N:1]2[C:35](=[O:34])[C:30]3=[CH:29][C:28]([F:27])=[CH:38][CH:37]=[C:31]3[C:32]2=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C1c2ccc(F)cc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A suspension of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (490 mg, 1.4 mmol) and 4-fluorophthalic acid anhydride (233 mg, 1.4 mmol) in xylene (3 mL) was stirred for 30 minutes at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, followed by recrystallization from dichloromethane-hexane to give 436 mg (yield 62%) of the titled compound, m.p. 235°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH:11]([CH:13]1[CH2:15][CH2:14]1)O)=[O:5])[CH3:2].[BrH:24]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH:11]=[CH:13][CH2:14][CH2:15][Br:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(O)C2CC2)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: Br
Solvent: CCO
Product: CCOC(=O)c1c(C=CCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 89.5 %

Procedure:
5-(Cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60a (323 mg, 1 mmol) was dissolved in 4 ml of ethanol under stirring, and added with hydrobromic acid (2.8 ml, 40%) to the solution and stirred for 30 minutes at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with saturated brine (15 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-(4-bromo-but-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60b (345 mg, yield 89.5%) as a white solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[CH:21]=[CH:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26].C(NCC)C.[C:34]1([O:40][C:41]([N:43]2[CH:56]([C:57]#[CH:58])[C:55]34[O:59][C:50]3([C:51](=[O:60])[CH2:52][CH2:53][CH2:54]4)[C:49]3[CH:48]=[CH:47][C:46]([O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:45][C:44]2=3)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1C=CC=CC=1.[Pd].[Cu]I>[C:34]1([O:40][C:41]([N:43]2[CH:56]([C:57]#[C:58]/[CH:21]=[CH:22]\[C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:55]34[O:59][C:50]3([C:51](=[O:60])[CH2:52][CH2:53][CH2:54]4)[C:49]3[CH:48]=[CH:47][C:46]([O:61][C:62](=[O:67])[C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:45][C:44]2=3)=[O:42])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3=O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCNCC
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(=O)C21O3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of Pd(PPh3 (4 (185 mg, 0.16 mmol), 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (0.776 g, 4.89 mmol), and diethylamine(0.51 L, 4.93 mmol) in degassed benzene (5 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 230 (1.50 g, 3.26 mmol) and CuI (124 mg, 0.65 mmol) in degassed benzene (15 mL) via a syringe followed by stirring at 25° C. for one hour. The reaction mixture was quenched by saturated aqueous NH4Cl, extracted with ethyl ether (80 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 25 percent ethyl ether in petroleum ether) provided a solid product Compound 231 (0.606 g, 32 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2964, 1721, 1494, 1378, 1305, 1270, 1253, 1202, 1181, 1122, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ8.40 (d, J=8.7 Hz, 1 H, H1), 7.44-7.10 (m, 6 H, H4 and aromatic), 6.99 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.98 (d, J=1.5 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.69 (br d, J =11.1 Hz, 1 H, olefinic), 2.81-2.66 (m, 2 H, H9), 2.41-2.26 (m, 2 H, H7), 2.10-1.86 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), 0.22 (s, 9 H, SiC(CH3)3); MS (FAB+) m/e (rel intensity) 582 (M+H, 100), 525 (13), 460 (48), 406 (8), 360 (6(),320 (8), 279 (25), 246 (5); HRMS for C34H36NO6Si (M+H), calcd 582.2312, found 582.2322.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3[nH]cnc23)CC1
Yield: 36 %

Procedure:
A solution of 6-chloro-9H-purine (1.19 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate. Suspension of the pre-purified material in ethyl acetate and filtration provided 0.89 g (36%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.31-1.43 (m, 2H), 1.40 (s, 9H), 1.87-1.90 (m, 2H), 2.74-2.88 (m, 2H), 3.92-3.96 (m, 2H), 4.32 (br s, 1H), 7.52 (br s, 1H), 8.08 (s, 1H), 8.18 (s, 1H). MS (ISP): 319.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:28][CH:29](O)[CH2:30][OH:31])([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O1CCOCC1.O>[Si:1]([O:8][CH2:9][C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:28][CH2:29][CH:30]=[O:31])[CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)CC(O)CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC=O)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2,3-Dihydroxypropyl)-2-(N-t-butoxycarbonylamino)-1,3-propanediol bis-t-butyldimethylsilyl ether (4.3 g) was dissolved in 600 ml of 1,4-dioxane and a solution of 3.8 g of meta-sodium periodate in 90 ml of water was added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and hexane was added thereto. After washing with water, the resultant mixture was dried and concentrated to give 3.76 g of colorless, oily 2-(N-t-butoxycarbonylamino)-2-(2-formylethyl)-1,3-propanediol bis-t-butyldimethylsilyl ether.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>CN(C=O)C>[CH3:26][O:25][C:21]([C:22]1[S:23][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:24]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (6.45 g, 32.9 mmol) and K2CO3 (5.45 g, 39.4 mmol) in DMF (60 mL) was slowly added methyl thioglycolate (3.0 mL, 32.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 2 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The solid was filtered and triturated with hot MeOH. The pale brown solid was filtered. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H). MS (EI): cal'd (MH+) 238.01, exp (MH+) 238.10.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24](B(O)O)=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[C:25]([O:27][CH3:28])=[N:26][C:21]([O:20][CH3:19])=[N:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 77.2 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (171 mg, 0.94 mmol) were reacted. After purification the title compound (133 mg, 78% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (bm, 1H), 8.31 (s, 1H), 7.89 (a dd, J=2.3, 7.4 Hz, 1H), 7.75 (m, 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=367, HPLC 2.07 min
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml), sulfuryl chloride (120 ml) was added dropwise at room temperature over 20 minutes, followed by stirring at the same temperature for 3 hours. The reaction mixture was poured into ice water (500 ml), and a crystallized matter was collected by filtration, whereby 182.3 g of the title compound were obtained (yield: 92%).
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=1)[CH3:25]
Reactant: CCOc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccnc(-c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis (tert-butoxycarbonyl)-N″-(3-(4-ethoxypyridin-2-yl)phenyl)guanidine (200 mg) in dichioromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(4-ethoxypyridin-2-yl)phenylguanidine dihydrochloride (126 mg).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C[N:33]1[CH2:38][CH2:37][O:36][C:35]2[CH:39]=[C:40]([S:43](Cl)(=[O:45])=[O:44])[CH:41]=[N:42][C:34]1=2>>[CH2:30]([O:29][CH2:28][C@@:10]12[CH2:9][N:8]([S:43]([C:40]3[CH:41]=[N:42][C:34]4[N:33]=[CH:38][CH2:37][O:36][C:35]=4[CH:39]=3)(=[O:45])=[O:44])[CH2:17][CH2:16][C:15]1=[CH:14][C:13]1[N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:12]=1[CH2:11]2)[CH3:31]
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: CN1CCOc2cc(S(=O)(=O)Cl)cnc21
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cnc3c(c1)OCC=N3)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonyl chloride. LCMS (Method C): 540 (M+H)+, Retention time 11.9 minutes.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][OH:18].O>CO>[OH:18][CH2:17][CH2:16][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CCc2c(cccc2OCCO)N1
Yield: 16.5 %

Procedure:
4.2 Grams of potassium hydroxide were dissolved in 200 ml of methanol, then 10 g of 5-hydroxy-3,4-dihydrocarbostyril were added thereto. Next, 10 g of 2-bromoethanol were added dropwise thereto under refluxing conditions. The reaction mixture was further refluxed for 4 hours, then was concentrated. To the residue thus obtained was added water, and the insoluble matter was collected by filtration, and was washed with water, then recrystallized from methanol to yield 2.1 g of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 176°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:11]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[N:11]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(OC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(OC)cc1F
Yield: 93.6 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(2-fluoro-4-methoxyphenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.072 g; 0.173 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h to afford 0.065 g (89%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:47]1[C:52](=[O:53])[CH2:51][CH2:50][C:48]1=[O:49])=[N+](C)C)C>>[O:49]=[C:48]1[CH2:50][CH2:51][C:52](=[O:53])[N:47]1[O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1

Procedure:
4-(15-tert-Butoxycarbonylpentadecanoylamino)-benzoic acid (29 mg, 0.063 mmol) was converted to the succinimidyl ester using TSTU similar to described above.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[F:14][CH:15]([F:19])[C:16](O)=O>O>[F:14][CH:15]([F:19])[C:16]1[NH:8][C:7]2[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[N:1]=1
Reactant: O=C(O)C(F)F
Reactant: COc1cc([N+](=O)[O-])cc(N)c1N
Solvent: O
Product: COc1cc([N+](=O)[O-])cc2[nH]c(C(F)F)nc12
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 2,3-diamino-5-nitroanisole (Horner et al., Annalen 1953, 579, 212) (1.10 g, 6 mmol) and difluoroacetic acid (2.31 g, 24 mmol) in polyphosphoric acid (PPA) (50 g) was heated at 130° C. in an oil bath for 1 hr. The hot solution was poured into water, and the pH was adjusted to neutral with cooling to give 2-(difluoromethyl)-4-methoxy-6-nitro-1H-benzimidazole (1.33 g, 91%): mp (EtOH/H2O) 192-194° C.; 1H NMR (DMSO-d6) δ 14.18 (br, exchangeable with D2O, 1H), 8.18 (br, 1H), 7.65 (dd, J=1.4 Hz, 1H), 7.30 (t, JHF=52.9 Hz, 1H), 4.07 (s, 3H); Anal. Calcd. for C9H7F2N3O3: C, 44.45; H, 2.9; N, 17.3. Found: C, 44.75; H, 3.0; N, 17.3%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]
Reactant: Fc1cccc(F)n1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2cccc(F)n2)CC1
Yield: 99.9 %

Procedure:
A solution of 2,6-difluoropyridine (9.0 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in acetonitrile (100 ml) was refluxed under heating for 18 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (8.7 g). The obtained pale-brown solid was crystallized from ethyl acetate-hexane to give the title compound (5.5 g) as pale-brown crystals.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[C:22](Cl)([CH3:24])=[O:23]>C1([N+]([O-])=O)C=CC=CC=1>[C:22]([C:14]1[CH:13]=[CH:12][C:10]2[C:11]3[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[C:6]=3[CH:7]=[CH:8][C:9]=2[CH:15]=1)(=[O:23])[CH3:24]
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c3c(ccc2c1)N(C(=O)C(F)(F)F)CC3CCl
Yield: 33 %

Procedure:
Acylation of 108 (0.88 g, 2.8 mmol) with AlC3 and AcCl in PhNO2 at 0° C., stirring at room temperature for 16 h, and workup as above, gave a crude product. Chromatography on silica gel, eluting with EtOAc/petroleum ether (from 0:1 to 1:3) gave 7-acetyl-1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (110) (196 mg, 33% based on consumption of starting material): mp (EtOAc/petroleum ether) 168-170° C.; 1H NMR (CDCl3) δ 8.52 (d, J=8.9 Hz, 1H), 8.51 (s, 1H), 8.14 (dd, J=8.8, 1.7 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.8H, 1H), 4.68-4.62 (m, 1H), 4.49-4.41 (m, 1H), 4.28-4.19 (m, 1H), −3.99-3.93 (m, 1H), 3.61-3.55 (m, 1H), 2.74 (s, 3H); 13C NMR δ 197.6, 182.8, 154.9 (q, JC-F 38.4 Hz), 142.1, 134.1, 132.2, 131.3, 131.1, 125.7, 125.5, 131.1, 118.1, 116.0 (q, JC-F 288 Hz), 52.7, 45.4, 42.6, 26.6. Anal. (C17H13ClF3NO2) C, H, N. Further elution gave recovered 108 (360 mg, 40%).