Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1.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>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>CO>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: Cc1ccc(CC2CCN(C(=O)CCl)CC2)cc1
Solvent: CO
Product: Cc1ccc(CC2CCN(C(=O)CNc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-methyl-benzyl)-piperidin-1-yl]-ethanone (Example 227a) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 206. Melting Point: 212-215° C. (methanol)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[C:4]([Cl:11])[N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:20])=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNc1cc(Cl)nc(N)n1
Solvent: CCO
Product: CCNc1cc(Cl)nc(N)[n+]1[O-]
Reaction time: 2 h
Yield: 34.9 %

Procedure:
8 g of 2-amino-4-ethylamino-6-chloropyrimidine are suspended in 150 ml of ethanol. 21.80 g of meta-chloroperbenzoic acid are added dropwise as solution in 150 ml of ethanol. After 2 hours' stirring, the reaction mixture is concentrated to a third in a rotary evaporator. The precipitate is filtered off on sintered glass, washed with 2×50 ml of ethyl ether and is then recrystallized from 60 ml of a 9/1 acetonitrile-ethanol mixture. 3.05 g of 2-amino-4-ethylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [OH:1][C@:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH:7]([CH3:9])[CH3:8])[CH2:3][C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C[O:34][CH2:33][CH2:32]1>>[OH:6][C:4]1[CH2:3][C@@:2]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH:7]([CH3:9])[CH3:8])[O:1][C:33](=[O:34])[CH:32]=1
Reactant: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]-4-methyl-pentanoic acid (0.45 g, 1.78 mmol) from Example UUUU, THF (10 mL), and CDI (0.58 g, 3.58 mmol). The reaction was stirred overnight at room temperature then added to bis[3-ethoxy-3-oxopropanoato(1-)-O,O']-magnesate (1.5 g, 5.2 mmol) from Example VVVV and the reaction stirred for 3 days at room temperature. The reaction was concentrated and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C([Si](C)(C)[O:26][C@H:27]1[CH2:31]C[N:29](/[CH:32]=[CH:33]/[NH:34][C:35](=[NH:38])[CH:36]=[CH2:37])[CH2:28]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:28][CH:27]([OH:26])[CH2:31]4)=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: C=CC(=N)N/C=C/N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC(O)C4)cn3)nc2n1C1CCCC1
Yield: 10.6 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (120 mg, 0.411 mmol) and N-{(E)-2-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-vinyl}-acrylamidine (112 mg, 0.401 mmol), followed by deprotection with 2 mL of TBAF to give 7-cyclopentyl-2-[5-(3-hydroxy-azetidin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (18 mg, 46%). MS (ESI) m/z 422.5 (M+H)+
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][CH:23](OC)[CH:24]=[CH2:25].[OH-].[Na+]>O.C(OCC)C>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH2:25][CH2:24][CH:23]([O:22][CH3:21])[O:5]2)=[CH:7][CH:8]=1
Reactant: C=CC(OC)OC
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC1CCc2ccc(O)cc2O1
Reaction time: 4 h
Yield: 43 %

Procedure:
A 500-milliliter flask fitted with a dropping funnel was charged with 11.0 g of resorcinol, 0.2 g of p-toluenesulfonic acid monohydrate and 100 ml of diethyl ether for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 13.0 ml of acrolein dimethyl acetal under room temperature. After the dropwise addition, the mixture was stirred for 4 hours while being cooled with ice. To this was added 30 ml of water, the solution was weakly alkalized with a 5% sodium hydroxide aqueous solution, and the organic layer was then washed. After the separation of layers in the solution, the aqueous layer was extracted three times with 50 ml of diethyl ether, and thus obtained ether layers were combined with the previous organic layer. The combined layer was washed with 50 ml of water, and diethyl ether was then removed by distillation in vacuo therefrom. The resulting residue was purified by distillation to obtain 7.7 g of a colorless liquid (yield 43%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12](=[O:15])[NH:13][N:14]=2)=[CH:4][C:3]=1[CH3:25].[Br:26]N1C(=O)CCC1=O>CC(C)=O>[Br:26][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:25])[CH:4]=2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Solvent: CC(C)=O
Product: Cc1cc(-c2cc(-c3[nH]c4ccccc4c3Br)c(=O)[nH]n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10 mg of 6-(4-hydroxy-3,5-dimethyl-phenyl)-4-(1H-indol-2-yl)-2H-pyridazin-3-one is dissolved in 400 μl of acetone and 5.3 mg of N-bromosuccinimide is added. The solution is stirred at RT for 20 min and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 4 mg. LC-MS (ES+) 409/411 (M)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH3:20].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([N:19]([CH2:18][CH2:17][Cl:16])[CH3:20])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CCCl)C1CC(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 1 of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c2c1CCC2=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O

Procedure:
Into a solution of 25.6 g of 4-methyl-7-hydroxy-1-indanone in 250 ml of acetic acid was added 19.4 ml of acetic anhydride and a solution of 15.4 ml of concentrated nitric acid in 50 ml of acetic acid gradually. The reaction mixture was concentrated to drynsss, and the residue was washed with ether to obtain 25.7 g of 4-methyl-6-nitro-7-hydroxy-1-indanone.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)C>[C:6]([C:5]1[C:8](=[NH:9])[N:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]2=[N:10][CH:4]=1)#[N:7]
Reactant: Cc1cccnc1N
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: Cc1cccn2c(=N)c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To 200 ml of ethanol were added 11.8 g (97 mmoles) of ethoxymethylenemalononitrile and 10.5 g (97 mmoles) of 2-amino-3-methylpyridine, and the reaction was carried out with stirring at room temperature for 2 hours. After completion of the reaction, the crystals precipitated were collected by filtration to obtain 13.5 g of 3-cyano-4-imino-9-methyl-4H-pyrido[1,2-a]pyrimidine. Yield: 76%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[OH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37](O)=[O:38])=[CH:32][CH:31]=[CH:30]2>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:37]([C:33]4[C:34]5[C:29](=[CH:28][C:27]([OH:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][CH:32]=4)=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cc(O)ccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 6-hydroxynaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11]2=[O:20])=[CH:7][CH:6]=1.[CH3:23][O:24][C:25](=[O:36])[CH:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:27]>>[CH3:23][O:24][C:25](=[O:36])[CH:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:27][C:17](=[O:19])[CH2:16][N:12]1[C:13](=[O:15])[CH2:14][CH:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:22][CH:21]=2)[C:11]1=[O:20]
Reactant: NN=Cc1ccc(CC2CC(=O)N(CC(=O)O)C2=O)cc1
Reactant: COC(=O)C(N)CCc1ccccc1
Agent: Cl
Product: COC(=O)C(CCc1ccccc1)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O

Procedure:
403 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acid hydrochloride are coupled with 270 mg of D,L-homophenylalanine methyl ester by the process described above. After working up and chromatographic purification, 343 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}-acetyl-D,L-homophenylalanine methyl ester are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=O)[NH:15]3)[CH:13]=2)[CH:5]=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[S:37])[NH:15]3)[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cncc(Cl)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cncc(Cl)c3)ccc2F)C1(F)F
Yield: 86.3 %

Procedure:
The reaction of (R)-5-[5-(5-chloro-pyridin-3-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 589 μmol) with Lawesson's reagent (238 mg, 589 μmol) in 1,4-dioxane (19.6 ml) yielded the (R)-5-[5-(5-chloro-pyridin-3-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (211 mg, 86% yield) as a white solid. MS (ISP): m/z=415.1 [M+H]+ and 417.1 [M+2+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N:23]1([CH2:22][CH2:21][N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: ICCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCOCC1)CCC2
Temperature: 70 °C
Yield: 7.2 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (246 mg, 1.38 mmol) in DMF (2.7 ml) was added potassium carbonate (574 mg, 4.15 mmol) followed by a solution of 4-(2-iodoethyl)morpholine (500 mg, 2.07 mmol) in DMF (2 ml) and the reaction heated to 70° C. After cooling to ambient temperature the reaction mixture was diluted with water and extracted with EtOAc which was washed with water, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 80% EtOAc/petroleum ether gave the title compound as an orange gum (29 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (d, 1H), 3.73 (m, 4H), 3.47 (m, 2H), 3.38 (m, 2H), 2.79 (t, 2H), 2.49-2.59 (m, 6H), 1.96 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]1[C:50]([NH:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:49]([NH2:71])[CH:48]=[N:47]1>C(Cl)Cl.O>[C:19]([O:18][C:16]([NH:15][CH2:14][CH:10]([C:11]([NH:71][C:49]1[CH:48]=[N:47][N:46]([CH3:45])[C:50]=1[NH:51][C:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:13])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
To a solution of 3-[(tert-butoxycarbonyl)amino]-2-{[(tert-butoxycarbonyl)amino]methyl}propanoic acid (476 mg) in methylene chloride (6 ml) were added hydroxybenzotriazole (222 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (573 mg), and the mixture was stirred for 10 minutes. 1-Methyl-N5-trityl-1H-pyrazole-4,5-diamine (530 mg) was added to the above mixture, and the whole mixture was stirred at room temperature for 1 hour. Water was added to the mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give tert-butyl (2-{[(tert-butoxycarbonyl)amino]methyl}-3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (270 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:17]=[O:18].Cl>O1CCCC1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)ccc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1F
Reaction time: 0.5 h

Procedure:
5-Bromo-2-fluoro-toluene (26 mmol, 5.0 g) was dissolved in tetrahydrofuran (25 ml) and cooled to −78° C. t-Butyllithium (1.7 M in pentane, 31 ml) was added over 10 minutes. After 30 minutes, N,N-dimethylformamide (2.1 ml) was added. The reaction mixture was warmed to ambient over 30 minutes and 6% HCl (100 ml) was added with vigorous swirling. The mixture was extracted with ethyl acetate (200 ml). The organic layer was dried over MgSO4, then concentrated affording the title compound as an oil (3.6 g, ˜quant.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([NH2:17])=[C:6]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=[NH:8].[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)#N.C(O)C>C(N(CC)CC)C>[CH3:16][O:15][C:11]1[CH:10]=[C:6]2[C:5](=[C:4]([O:3][CH3:2])[C:12]=1[O:13][CH3:14])[N:17]=[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[N:8]=[C:7]2[NH2:9]
Reactant: COc1cc(C(=N)N)c(N)c(OC)c1OC
Reactant: CCOC(=O)N1CCN(C#N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)c(OC)c3n2)CC1

Procedure:
A solution containing 2.62 g. (0.01 mole) of 3,4,5-trimethoxy-2-aminobenzamidine hydrochloride and 1.83 g. (0.01 mole) of 1-cyano-4-ethoxycarbonylpiperazine in 50 ml. of anhydrous ethanol is stirred at ambient temperature overnight. A 5-ml. aliquot of triethylamine is then added and the reaction mixture is heated under reflux for 12 hours. It is then worked up as described in Example XI, giving 6,7,8-trimethoxy-4-amino-2-[4-ethoxycarbonylpiperazin-1-yl]quinazoline.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:11]([C:12]1[CH:4]=[CH:3][C:2]([C:7]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH:6]=2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: Oc1ccccc1I
Reactant: c1ccncc1
Product: CCc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A flask containing 5.4 g. (0.028 mol.) of cuprous 4-ethylphenylacetylide in 100 ml. of pyridine is thoroughly flushed with nitrogen. A solution of 6.19 g. (0.028 mol.) of o-iodophenol in 50 ml. of pyridine is added under nitrogen and the reaction mixture is stirred and heated at 120° for 22 hours. The pyridine is removed by distillation in vacuo, the residue is added to an ice-water mixture and the gummy precipitate is collected and dissolved in methylene chloride. The methylene chloride solution is washed with 3N hydrochloric acid and water and concentrated under reduced pressure to give a residue which is chromatographed on a silica gel "dry-column" to give 2-(4-ethylphenyl)benzofuran.
Reaction SMILES: Cl[C:2]1C=CC(OC)=C([CH:42]=1)C[C@H]1CN2C(O)=NN=C2CN(C(N[C@@H](C2C=CC(C(OC(C)(C)C)=O)=C([N+]([O-])=O)C=2)CC)=O)C1=O.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:84][CH3:85])=[C:50]([CH:83]=1)[CH2:51][C@H:52]1[CH2:58][N:57]2[C:59]([OH:62])=[N:60][N:61]=[C:56]2[CH2:55][N:54]([C:63]([NH:65][C@@H:66]([C:69]2[CH:70]=[C:71]([CH:79]=[CH:80][CH:81]=2)[C:72]([O:74]C(C)(C)C)=[O:73])[CH2:67][CH3:68])=[O:64])[C:53]1=[O:82]>>[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:84][CH3:85])=[C:50]([CH:83]=1)[CH2:51][C@H:52]1[CH2:58][N:57]2[C:59](=[O:62])[N:60]([CH2:2][CH3:42])[N:61]=[C:56]2[CH2:55][N:54]([C:63]([NH:65][C@@H:66]([C:69]2[CH:70]=[C:71]([CH:79]=[CH:80][CH:81]=2)[C:72]([OH:74])=[O:73])[CH2:67][CH3:68])=[O:64])[C:53]1=[O:82]
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)OC(C)(C)C)c1
Product: CC[C@@H](NC(=O)N1Cc2nn(CC)c(=O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)O)c1

Procedure:
Instead of the starting material, that is, the compound 91a, of Example 91, Step (2), the compound 92a was used for a similar procedure as in Example 91, Step (2) and Example 87, Step (3) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N)sc1C
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1sc(=N)n(CCN2CCOCC2)c1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (1.0 g, 7.8 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.6 g, 8.6 mmol) and triethylamine (2.4 mL, 17.2 mmol) were heated at 80° C. After 3 hours, additional triethylamine (1.1 mL, 7.9 mmol) was added and the mixture was stirred at 80° C. for 14 hours, then cooled to ambient temperature and concentrated. The residue was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate and water. The organic extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 0.26 g (14%) of a 3:1 mixture of title compound to 4,5-dimethyl-thiazol-2-ylamine. MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([OH:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:16]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:13]=[CH:12]2)([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Reactant: CC(C)(C)OC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cccc(OCCCCCC(=O)OC(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of 8-hydroxyquinaldic acid methyl ester (406 mg, 2 mmol, 1 eq.) and t-butyl-6-bromohexanoate (754 mg, 3 mmol, 1.5 eq.) in DMF (5 mL) was added potassium carbonate (828 mg, 6 mmol, 3 eq.). The mixture was stirred vigorously for 3 h at 60° C., and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. Crude product was purified by flash chromatography on silica using ethyl acetate:hexanes gradient to provide 617 mg of 1. Yield 86%. MS m/z 374 (M+H)+