Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([O:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35](=[O:48])[NH:36][C:37]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=3[F:47])[CH:30]=[CH:29]4)=[N:20][CH:19]=[N:18][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:37]=1[NH:36][C:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([O:25][C:21]3[C:22]4[CH2:23][CH2:24][NH:15][CH2:16][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(F)(F)F)ccc3F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21

Procedure:
TFA (1 mL, 13.0 mmol) is added to a solution of 4-[1-(2-fluoro-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.125 g, 0.219 mmol) and DCM (2.5 mL). After 1 h the solution is concentrated in vacuo. The residue is taken up in MeOH and neutralized to pH 7 by the addition of NH4OH and the solution is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give 5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-5-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 472.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.07 (d, J=3.8 Hz, 1H), 8.03-8.07 (m, 1H), 7.67-7.75 (m, 1H), 7.56-7.64 (m, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 3.83 (s, 2H), 3.04 (t, J=5.8 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]([F:26])[CH:7]=1)=[O:5])[CH3:2].[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[C:8]([F:26])[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[F:12])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNC(=O)c1cc(F)c(N2CCNCC2)cc1F
Reaction time: 0.5 h
Yield: 98 %

Procedure:
tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (0.020 g, 0.054 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (16.2 mg, 0.053 mmol, 98% yield) as a white solid. ESI-MS:m/z 270 (M+H)+.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:11][C:12]1[CH:19]=[C:18]([N:1]2[CH:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CC[C@@H]2NCCC[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCCC3CCCCC32)cc1Cl
Yield: 68 %

Procedure:
A solution (2 mL) of cis-decahydroquinoline (447 mg), 2-chloro-4-fluorobenzonitrile (500 mg) and lithium carbonate (237 mg) in dimethyl sulfoxide was reacted at 140° C. for 10 min in a microwave reaction apparatus. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give the title compound as a colorless oil (yield: 600 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1.Cl[CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]=1[O:54][CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60]>>[CH3:60][Si:59]([CH3:61])([CH3:62])[CH2:58][CH2:57][O:56][CH2:55][O:54][C:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:52]=[CH:53][C:44]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Reactant: C[Si](C)(C)CCOCOc1c(CCl)ccc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2OCOCC[Si](C)(C)C)C1

Procedure:
(cc) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate [Example 22(h)] with 2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 6(c)] there was obtained tert-butyl (3RS,4RS)-3-[1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate. Selective cleavage of the trityl group analogously to Example 86(u) (β) gave tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-[1-(2-trimethylsilanyl-ethoxymethoxy)naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, acylation of which with 3-methoxy-benzoyl chloride analogously to Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-(3-methoxy-benzoyloxymethyl)-phenyl]-3-[1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil, MS: 745 (M+NH4)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:55].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[NH:55][C:28]([CH:29]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH:46]4[CH2:47][CH2:48]4)(=[O:44])=[O:45])=[CH:39][CH:38]=3)[CH2:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[N:22][N:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1)(c1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 1-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazol-2-yl]-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (168 mg) in acetic acid (2.3 mL) was added ammonium acetate (283 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (122 mg, yield 74%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (1.00 g, 4.65 mmol, 1.0 eq.) in degassed toluene (20 mL) was added ethyl diazoacetate (0.98 mL, 9.30 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 2 hours the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-40% ethyl acetate in hexanes) to afford ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.64-2.55 (m, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 2.36 (ddd, 1H, J=8.6, 5.7, 3.8 Hz), 1.74-1.61 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). LRMS m/z (M+H+) 302 found, 302 required.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([N+:35]([O-:37])=[O:36])[CH:21]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:21]=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:25]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Yield: 39.6 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4(226 mg, 0.2 mmol) and K3PO4(2.76 g, 13 mmol) in DME/H2O (5 ml/ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130° C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[F:34][C:35]([F:56])([F:55])[O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][C:35]([F:56])([F:34])[F:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: FC(F)(F)OCCn1c(NC2CCNCC2)nc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3CCOC(F)(F)F)CC2)(c2ccccc2)C1
Reaction time: 48 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.86 g, 1.83 mmol), (1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydrochlorici acid salt (1.66 mmol), triethylamine (1.0 mL, 7.2 mmol), and sodium iodide (0.31 g) in acetonitrile (24 mL). Heat to reflux. After 48 hours, evaporate in vacuo to give a residue. Partition the residue between dichloromethane and a saturated aqueous sodium, bicarbonate solution. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)(=O)C.[OH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C=O)C>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(=O)OCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCCO)cc1
Temperature: 90 °C
Reaction time: 11 h
Yield: 89.5 %

Procedure:
276.6 g of 4-chlorobutyl acetate (1.8 mol) were added to a solution of 249 g of ethyl 4-hydroxybenzoate (1.5 mol), 3 g of potassium iodide (0.018 mol) and 248 g of potassium carbonate (1.8 mol) in 21 of DMF, and the mixture was stirred at 90° C. for 11 hours. The reaction mixture was poured into 5 l of ice-water, and the precipitate was filtered off with suction and washed with 41 of ice-water. The crude product was dissolved in 3 l of ethanol, potassium hydroxide (400 g) was added, and the mixture was refluxed for 3 hours. The reaction mixture was poured into 6 l of ice-water and acidified using concentrated hydrochloric acid, and the precipitate was filtered off. The precipitate was washed with water until neutral and subsequently dried, giving 282.1 g of 4-(4′-hydroxybutoxy)benzoic acid (yield 89%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Reactant: CN1CCNCC1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)N1CCN(C)CC1
Yield: 91.1 %

Procedure:
2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol) and 1-methylpiperazine (0.06 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.23 g, 90.5% yield).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19](OC)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc(-n2cccc2C#N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccn1-c1cccc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
28% Methanolic sodium methoxide (122.2 ml) was added to a solution of guanidine hydrochloride (63.7 g) in dry N,N-dimethylformamide (300 ml) and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.5 g), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water under stirring. The isolated precipitate was collected by filtration to give 2-[3-(2-cyanopyrrol-1-yl)benzoyl]guanidine (21.66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])=[O:7].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[N:8]([CH3:31])[C:6](=[O:7])[C:5]2[CH:32]=[CH:33][C:34]([NH:35][C:36]([C:38]3[C:46]4[N:45]=[C:44]([CH2:47][NH:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[NH:43][C:42]=4[CH:41]=[CH:40][CH:39]=3)=[O:37])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:23])[CH2:29][CH2:28]1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(O)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg) in methanol (5 ml) was added sodium borohydride (7.52 mg) under an ice bath cooling and the mixture was stirred at the same temperature for 1 hour. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-[2-[5-(4-hydroxypiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]-3-methoxy-N-methyl-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CCO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(N[C@@H](COCC1CCN(c2ccncc2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Temperature: 120 °C

Procedure:
To a suspension of 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (1.0 g, 2.2 mmol) in 20 mL of EtOH was added triethylamine (1.56 mL, 11 mmol) and 4-chloropyridine hydrochloride (336 mg, 2.2 mmol). Heating the mixture at 120° C. in a sealed tube afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 185 mg (16%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].[CH:14]([N:17](C(C)C)CC)(C)[CH3:15].Cl.C(N)C>C(#N)C>[Br:13][C:9]1[N:10]=[C:11]2[N:17]([CH2:14][CH3:15])[CH2:2][C:3](=[O:4])[NH:5][C:6]2=[N:7][CH:8]=1
Reactant: O=C(CBr)Nc1ncc(Br)nc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: Cl
Solvent: CC#N
Product: CCN1CC(=O)Nc2ncc(Br)nc21
Temperature: 70 °C
Yield: 36 %

Procedure:
To a solution of 2-bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (See Example 4.A) (1 equiv) and diisopropylethylamine (3 equiv) in acetonitrile was added ethanamine hydrochloride (1.05 equiv). The solution was allowed to heat to 70° C. for 30 min. The solution was condensed under reduced pressure and purified using column chromatography (0-75% ethyl acetate in hexanes) to afford the title compound in 36% yield. MS (ESI) m/z 257.5 [M]+, 259.4 [M+2]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1
Reactant: COC(=O)COCCCl
Reactant: Brc1ccc2c(c1)Cc1ccccc1C1CNCCN21
Product: COC(=O)COCCN1CCN2c3ccc(Br)cc3Cc3ccccc3C2C1
Yield: 38 %

Procedure:
Following a procedure similar to that described in Example 1, but using 8-bromo-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and methyl 2-chloroethoxyacetate, the title compound was obtained in a yield of 38%.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:11]>>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Product: Cc1ccc(NC(=O)C(C)C)cc1Br

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 3-bromo-4-methylaniline: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1

Procedure:
Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (Ig, 7 mmol) and 1-Boc-piperazine (1.9 g, 10 mmol) 1H NMR (400 MHz, CDCl3) δ (ppm): 7.03 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.2 Hz, 1H), 6.23 (m, 2H), 3.62 (br, 2H), 3.53 (m, 4H), 3.07 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([NH2:29])([CH3:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CC1(N)CNC1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(F)c(F)c1n2C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2c(F)cc3c(=O)c4c(=O)[nH]sc4n(C4CC4)c3c2F)C1
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.8 mmol) of 9-cyclopropyl-6,7,8-trifluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, 255 mg (1.6 mmol) of 3-methyl-3-aminoazetidine dihydrochloride and 0.6 ml of triethylamine in 10 ml of pyridine is kept refluxing for 2 hours, the mixture is evaporated under vacuum, a mixture of ethanol with water is added, the resulting mixture is filtered and the product is washed. 0.225 g of 9-cyclopropyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 294°-300° C., is thereby obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16])(=O)=O.Cl>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[C@H:14]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Reactant: CNc1ccccc1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](c1ccccc1)N(C)c1ccccc1
Temperature: 120 °C
Yield: 26.6 %

Procedure:
N-methylaniline (299 ul, 2.76 mmol) is added to a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (450 mg, 1.84 mmol) in acetonitrile (10 mL). The reaction is heated at 120° C. for 15 minutes (microwave irradiation). 2N HCl (5 mL) is added and the mixture is extracted with EtOAc. The organic phase is dried over sodium sulphate and the solvent is evaporated to dryness. The crude is purified by flash chromatography on silica gel (Petroleum ether/Et2O=9/1) to obtain intermediate I121 as an orange amorphous solid (125 mg, 27% yield).