Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]2=[N:4][CH:3]=1.CS[C:17]1[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH:19][N:18]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:17]2[N:18]=[C:19]([C:2]3[N:6]4[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]4=[N:4][CH:3]=3)[CH:20]=[CH:21][N:22]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: OCCNc1nccn2c(Br)cnc12
Product: OCCNc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
2-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol was prepared by a process analogous to that described in Example 12 starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (from Example 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and morpholine. LC-MS: [M+H]+ 342.3.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:18])=[CH:7][CH:8]=2)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O.O>C(O)C>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:16]1[C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([Br:18])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1S
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3nc4ccccc4s3)cc21
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (Example 3; 49.35 g, 0.15 mol), 2-aminothiophenol (20 mL, 0.187 mol, 1.25 eq.), and DMSO (110 mL) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 mL), filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g, were then reslurried in hot ethanol (600 mL) cooled and filtered to get the product, 45.69 g, m.p. 133.6-135° C. An additional 6.6 g, m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Analysis: Calculated for C24H20BrNS: C, 66.37%; H, 4.64%; Br, 18.40%; N, 3.23%; S, 7.37%. Found: C, 66.46%; H, 4.52%; Br, 18.54%; N, 3.14%; S, 7.19%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([OH:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[C:37]([OH:39])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(O)cc(O)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(O)cc(O)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.097 g (0.172 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.026 g (0.688 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR73## is obtained (0.023 g, 29% ) as white foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.57, FD-MS: M+ =467.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[S:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15]([NH:29][CH3:28])[C:16]=3[S:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: CSc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1SC

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-methylthio-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg) was added to pyridine (100 mg). A 40% aqueous solution (120 mg) of methylamine was added, and the resultant mixture was stirred overnight at room temperature and for additional 2 days at 50° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol (1 ml) was added to the residue, and solids deposited were collected by filtration to obtain the title compound (25 mg) as a pale brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:16][C:17](=O)[CH2:18][C:19](OC)=[O:20].O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>CC#N>[Cl:16][C:17]1[N:15]=[C:13]2[S:14][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11][N:12]2[C:19](=[O:20])[CH:18]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1nnc(-c2cccc([N+](=O)[O-])c2)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(Cl)nc2sc(-c3cccc([N+](=O)[O-])c3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
In a particular instance, the compound of this example is prepared as described or similarly described as follows: To 5-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine (2) (3.0 g, 13.50 mmol) in MeCN (120 ml) is added methyl 3-chloro-3-oxopropanoate (1.735 mL, 16.20 mmol). The mixture is stirred at room temperature for 2 hours. After consumption of the starting material, POCl3 (60 mL, 644 mmol) is added along with DIPEA (2.358 mL, 13.50 mmol) in MeCN (10 mL). The mixture is heated in the microwave at 150° C. for 25 min, cooled, and concentrated in vacuo. The resulting slurry is taken up in chloroform, poured over ice and washed with saturated NaHCO3, water and brine, dried over MgSO4, and concentrated in vacuo to give a dark red oil which is purified via column chromatography on a 100 g snap column with 0-10% EtOAc/DCM gradient elution to give 7-chloro-2-(3-nitrophenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.36 g, 4.41 mmol, 32.6% yield) as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.CS(C)=O.[CH3:34][OH:35]>N1CCOCC1>[CH3:8][N:10]([CH3:11])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([N:7]2[CH2:6][CH2:5][O:35][CH2:34][CH2:2]2)=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: CN(C)c1ccc(N2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in morpholine (0.5 ml). The mixture was heated at 160° C. for 2 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (16 mg) as an orange solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:20])=[C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][C:8]2=[C:15]([C:18]#[N:19])[C:16]=1[CH3:17])=O.[C:21]([NH2:24])(=[S:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:13][N:12]([CH3:14])[C:10]1[O:11][C:7]2[C:8](=[C:15]([C:18]#[N:19])[C:16]([CH3:17])=[C:5]([C:3]3[N:24]=[C:21]([CH3:22])[S:23][CH:2]=3)[C:6]=2[F:20])[N:9]=1
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(N(C)C)nc2c1C#N
Reactant: CC(N)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
6-(Bromoacetyl)-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-170) (0.60 g, 1.76 mmol) was dissolved in toluene (30 ml), then thioacetamide (0.16 g, 2.13 mmol) and cesium carbonate (0.75 g, 2.30 mmol) were added, followed by stirring at an external temperature of 100° C. for 16 hours. The reaction liquid was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain a yellow solid (0.44 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(Br)ccc1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
To an ice-cold solution of 5-bromo-2(1H)-pyridone (1.0 g, 5.75 mmol) in DMF (5.0 mL) was added NaH (60% suspension in mineral oil, 0.25 g, 10.30 mmol) portion wise and the resulting solution was heated to 80° C. for 90 min. The reaction mixture was then again cooled to 0° C. followed by addition ethyl bromoacetate (1.92 g, 11.50 mmol). The reaction mixture was then heated to 80° C. for 16 h. After the completion of reaction (TLC monitoring), DMF was distilled off, added water and extracted with EtOAc (3×100 mL). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 20% EtOAc-hexane) to obtain the desired product (0.90 g, 60%). MS: 260.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(#N)C>[ClH:1].[Cl:1][C:2]1[C:19]([O:20][C:26](=[O:29])[CH2:27][CH3:28])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)Oc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Product: Cl
Reaction time: 2.5 h

Procedure:
Reflux a mixture of 6.70 g (0.0232) moles of (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 8.0 g of anhydrous sodium bicarbonate and 6.0 ml of propionyl chloride in 150 ml of dry acetonitrile with stirring for 2.5 hours and concentrate to dryness on a steam bath. Dissolve the residue in a mixture of 60 ml of water and 70 ml of ethyl ether. Separate the ether layer, dry over anhydrous sodium sulfate, filter and evaporate to dryness. Redissolve the residue in 150 ml of anhydrous ethyl ether and precipitate (S)-7-chloro-3-methyl-1-phenyl-8-propionyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride by slow addition of a slight excess of 1N ethereal hydrogen chloride. Obtain an analytical sample by crystallization from 2-propanol, m.p. 234°-236° C., [α]D26 =+32.5° (c=1, dimethylformamide).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Pd]>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1
Reactant: COC(=O)c1cccc(I)c1
Reactant: CCB(CC)c1cccnc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2cccnc2)c1
Reaction time: 10 h
Yield: 68.1 %

Procedure:
A mixture of diethyl(3-pyridyl)borane (176.4 g, 1.2 mole), methyl-3-iodobenzoate(262 g, 1 mole), potassium phosphate (318.4 g, 1.5 mole) and tetrakistriphenlyphosphine palladium (0) (57.8 g, 0.05 mole) in DMF (1000 ml) was heated at 80 degrees under argon. After 10 h, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was filtered and washed with water. To the organic fraction was added concentrated HCL (65 ml). The organic layer was separated and extracted with aqueous HCl . The combined acid extractions were treated with ethyl acetate, followed by 50% aqueous sodium hydroxide (55 ml). The organic layer was separated, washed with water and saturated sodium bicarbonate solution, then dried over sodium sulfate. The solution was filtered and concentrated to give methyl-3-(pyridin-3-yl)benzoate (145.3 g).
Reaction SMILES: [CH3:1][N:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[C:44]2[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=3)[CH:47]=[CH:46][N:45]=2)[N:25]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC2C=CC([N+]([O-])=O)=CC=2)=[O:12])[CH2:7][CH2:6]1.[CH3:65][O:66][CH2:67][CH2:68][NH2:69].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:65][O:66][CH2:67][CH2:68][NH:69][C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:34][C:33]=3[C:44]3[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:60])([F:62])[F:61])[CH:54]=4)[CH:47]=[CH:46][N:45]=3)[N:25]=2)[CH2:10][CH2:9]1)=[O:12]
Reactant: COCCN
Reactant: CN(CCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-nitrophenyl 4-(2-(methyl((6-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)pyridin-2-yl)methyl)-amino)ethyl)piperazine-1-carboxylate (100 mg, 0.11 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 2-methoxyethanamine (10 mg, 0.13 mmol, 1.00 equiv), and N,N-diisopropylethylamine (45 mg, 0.35 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The crude product (0.1 g) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 23.2 mg (18%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.76 (s, 1H), 9.54-9.52 (m, 1H), 9.05-9.03 (m, 1H), 8.48-8.45 (m, 1H), 8.26 (m, 1H), 8.14-8.12 (m, 2H), 7.88-7.86 (m, 1H), 7.79-7.24 (m, 7H), 6.71 (m, 1H), 4.65-4.63 (d, J=5.7 Hz, 2H), 4.09 (m, 3H), 3.69-3.01 (m, 23H), 1.71-1.59 (m, 6H). MS (ES, m/z): 816 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:5]=1[CH3:13].CO[CH:17]([N:20]([CH3:22])[CH3:21])OC.[CH3:23]N(C=O)C>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:23])[C:5]=1[CH:13]=[CH:17][N:20]([CH3:22])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Product: COC(=O)c1cccc(C)c1C=CN(C)C
Temperature: 110 °C

Procedure:
2-Methyl-3-nitro-benzoic acid methyl ester (5.0 g, 25.6 mmol) was combined with dimethoxymethyl-dimethyl-amine (10.2 mL, 76.8 mmol, 3.0 eq.) and DMF (25 mL) and heated to 110° C. overnight. The reaction mixture was then concentrated in vacuo to yield crude 2-(2-Dimethylamino-vinyl)-3-methyl-benzoic acid methyl ester.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]2[N:38]=[C:39]([CH:41]=O)[N:40]=[C:33]2[N:32]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:41][C:39]3[N:40]=[C:33]4[N:32]=[C:31]([CH3:30])[CH:36]=[C:35]([CH3:37])[N:34]4[N:38]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CO
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F
Reaction time: 12 h

Procedure:
A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (300 mg, 0.75 mmol) in anhydrous MeOH (3.0 mL) was treated with 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (198 mg, 1.1 mmol), followed by borane-dimethylamine complex (62 mg, 1.05 mmol) at room temperature. The reaction was stirred for 12 hours before it was quenched by the addition of CH2Cl2 (30 mL) and Amberlite IR 120(plus) (3 g). The reaction was stirred for 30 minutes, and then filtered. The filtrate was concentrated to an oil, dissolved in CH2Cl2 (25 mL, and then washed with 10 mL 1 N HCl. The aqueous layer was extracted with 2×25 mL CH2Cl2. The organic layers were combined and dried over Na2SO4. After removing the solids by filtration, the liquid was concentrated to an oil. The desired product was isolated by preparatory HPLC (76 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 0.74 (t, J=7.45 Hz, 6H), 1.37-1.59 (m, 8H), 1.79-1.88 (m, 4H), 1.94-2.03 (m, 2H), 2.21 (t, J=8.84 Hz, 3H), 2.36 (d, J=17.94 Hz, 1H), 2.47-2.55 (m, 5H), 2.59-2.63 (m, 4H), 3.95 (d, J=3.54 Hz, 2H), 6.66 (dd, J1=13.26 Hz, J2=1.64 Hz, 1H), 6.72-6.75 (m, 2H), 7.23 (t, J=8.21 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
4-Methylbenzaldehyde (20 g, 166 mmol), hydroxylamine hydrochloride (12.7 g, 183 mmol), and sodium acetate (23.1 g, 282 mmol) were dissolved in a mixed solvent of ethanol (400 ml) and water (150 ml), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20.6 g, 152 mmol, 91.8%).
Reaction SMILES: [NH2:1][C:2]1[C:26]([Cl:27])=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]([O:20]C(C)(C)C)=O)[CH2:12]2)=[O:7])=[C:4]([O:28][CH3:29])[CH:3]=1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:18]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:25]=[C:26]([Cl:27])[C:2]([NH2:1])=[CH:3][C:4]=3[O:28][CH3:29])[CH2:12]2)=[O:20])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(2-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-ethyl)-5-chloro-2-methoxybenzamide (0.97 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-N-(1-(2-(4-amino-5-chloro-2-methoxybenzoylamino)ethyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=C(C(O)=O)O[C:12]=1[Br:13].CN(C)C=O>ClCCl>[Br:7][C:8]1[CH:9]=[C:2]([C:1]([Cl:6])=[O:5])[O:3][C:12]=1[Br:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)c(Br)o1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (10.4 ml, 0.12 mol) was added to a suspension of 4,5-dibromo-2-furoic acid (27 g, 0.1 mol) in dichloromethane (300 ml) containing dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was re-dissolved in dichloromethane and concentrated in vacuo; this was repeated to give the title compound which was used directly in the following step.
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2ccoc12
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4ccoc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(benzofuran-7-yloxy)ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (1.4 g, 7.4 mmol) and triethylaniine (0.74 g, 7.4 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride) afforded 0.31 g (30%) of product as a light-brown oil.
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CO.C(OCC)C>[O:8]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOCC
Product: c1ccc(OCc2ccncc2)cc1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
To a solution of 3.5 g (0.15 mole) of sodium in 100 ml of methanol are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated, mixed with 50 ml of N,N-dimethyl formamide and 8.2 g (0.05 mole) of 4-chloromethylpyridine hydrochloride and the reaction mixture heated for 20 hours at 100° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with a dilute aqueous solution of sodium hydroxide and with water, dried over anhydrous sodium sulfate, evaporated and the residue distilled in a vacuum. There are obtained 8.2 g of 4-phenoxymethylpyridine (88% of theory); b.p. 115°-117° C./0.1 mm Hg.