Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[OH:26][C:27]1[CH:69]=[CH:68][C:30]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:33][CH:32]=2)=[CH:29][CH:28]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:35][CH:36]=2)=[CH:68][CH:69]=1)=[O:4]
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 25.1 %

Procedure:
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-octanoyl chloride (0.30 g, 0.7 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.40 g, 0.7 mmol) in DCM (30 mL) containing pyridine (2 mL) under N2 at 0° C. with stirring. The mixture was stirred at room temperature for 1 h, poured into HCl (2 M, 100 mL), extracted with DCM (3×50 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes) as eluent and the solvent removed under reduced pressure. The residue was dissolved in Et2O, hexane was added and the solvent reduced. The resulting precipitate was filtered to give the title compound (0.17 g, 25%) as a colourless powder, mp 144-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[C:13](OCC)(=[O:16])[NH:14][NH2:15]>CCO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]3[C:13](=[O:16])[NH:14][N:15]=[C:9]32)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: CCOC(=O)NN
Solvent: CCO
Product: O=c1[nH]nc2c3cc(Br)ccc3ccn12

Procedure:
7-Bromo-1-chloroisoquinoline (1-1) (79 mg, 0.327 mmol, 1.0 equiv) and Ethyl carbazate (34 mg, 0.33 mmol, 1.0 equiv) were suspended in EtOH (1.5 mL). The reaction mixture was irradiated in microwave at 170° C. for 40 minutes. The crude mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to yield 9-bromo[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (1-2). LRMS m/z (M+H) 263.9 and 264.9 found, 264.1 and 265.1 required.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:5][C@:4]1([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:21]O>C1(C)C=CC=CC=1>[CH3:21][O:7][C:6]([C@@:4]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:5][C@H:3]1[CH2:2][Br:1])=[O:8]
Reactant: CO
Reactant: O=C(O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CBr
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CBr
Temperature: 5 °C
Reaction time: 2 h

Procedure:
(1S,5R)-1-(3,4-Dichlorophenyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (22.6 g) was dissolved in 33% HBr/glacial acetic acid and heated to 80° C. for 5 h, cooled to rt and thrown into 1300 ml ice-water and stirred at rt for 16 h. The precipitated acid was isolated by filtration, redissolved in toluene (1000 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give 30 g of the intermediate (1S,2R)-2-(bromomethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid. The (1S,2R)-2-(bromomethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid (30 g) was dissolved in anhydrous toluene (200 ml) and thionylchloride (18 ml) was added dropwise during 15 min. after which the mixture was refluxed for 60 min. The reaction mixture was cooled to 5° C. and methanol (200 ml) was added and the mixture was allowed to warm to rt and stirred at rt for 2 h. The mixture was evaporated in vacuo, redissolved in diethylether, washed with saturated aqueous sodium hydrogen carbonate 25 ml), brine (25 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo. To give the intermediate (1S,2R)-2-(bromomethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid methyl ester (27 g). The (1S,2R)-2-(bromomethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid methyl ester (15 mmol) was dissolved in acetonitrile (50 ml) and added to a mixture an amine of formula III (15 mmol) in a mixture of acetonitrile (50 ml) and ethyl diisopropylamine (30 mmol). The mixture was stirred at room temperature for 16 h, evaporated in vacuo, taken up in ethyl acetate (200 ml) and washed successively with saturated sodium hydrogen carbonate (50 ml) and brine (50 ml, dried over anhydrous magnesium sulphate and evaporated in vacuo to give the crude product ester of formula VII. Esters of formula VII were generally purified by precipitation of the oxalate salt from acetone.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[C:5]2[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>C1(C)C=CC=CC=1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[C:5]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(Cl)ccc2n1
Reactant: NCc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(NCc3cccnc3)ccc2n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
(6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (185 mg, 0.492 mmol) was dissolved in 5 mL toluene and 1 mL tert. butanol. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (160 mg, 1.48 mmol), sodium tert.-butylate (95 mg, 0.99 mmol), palladium acetate (6 mg, 0.027 mmol) and 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 23 mg, 0.05 mmol) were added. The reaction mixture was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a yellow foam (105 mg, 47%), MS: m/e=448.3 (M+H+).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)#[CH:3]
Reactant: Nc1cccc2ccccc12
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1cccc2ccccc12)c1ccccc1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 1-napthylamine (0.170 g, 1.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.210 g, 83%). HPLC analysis indicated the enantiomeric excess of the product was 95% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99/1; flow rate=0.6 mL/min; detection wavelength=254 μm; TR=29.3 (minor), 40.3 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.68 (dd, J=8.4, 1.6 Hz, 1H), 7.62 (dd, J=7.6, 2.0 Hz, 1H), 7.30-7.03 (m, 9H), 6.39 (dd, J=6.6, 1.8 Hz, 1H), 5.97 (ddd, J=17.2, 10.4, 6.0 Hz, 1H), 5.18 (dt, J=16.8, 1.2 Hz, 1H), 5.10 (dt, J=10.0, 1.2 hz, 1H), 4.95 (d, J=6.0 Hz, 1H), 4.57 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 141.95, 141.57, 138.88, 134.17, 128.74, 128.67, 127.46, 127.08, 126.41, 125.61, 124.69, 123.37, 119.79, 117.59, 116.25, 106.20, 60.86. Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.07; H, 6.53; N, 5.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[NH2:12])[C:6]=2[CH:14]=1.[CH:15](=O)[CH3:16]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][N:8]=[C:7]([N:11]([CH3:13])[N:12]=[CH:15][CH3:16])[C:6]=2[CH:14]=1
Reactant: CC=O
Reactant: CN(N)C1=NOCc2ccc(Cl)cc21
Solvent: c1ccccc1
Product: CC=NN(C)C1=NOCc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
To a solution of 3 g. of 6-chloro-4-(1-methylhydrazino)-1H-2,3-benzoxazine in 180 ml. of anhydrous benzene 1 g. of acetaldehyde in 30 ml. of anhydrous benzene is added. The mixture is allowed to stand for 2 hours, then the solvent is distilled off in vacuo and the residue recrystallized from isopropyl ether. Yield 2.4 g. (71.2%) of 6-chloro-4-(2-ethylidene-1-methylhydrazino)-1H-2,3-benzoxazine; m.p. 111°-112° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:13][P:14](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.O>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][P:14]([CH3:13])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CP(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The methylphenylphosphinic acid 4-nitrophenyl ester is prepared in the following way: A suspension of 173 mg of NaH at 50% in oil, in 2 ml of anhydrous tetrahydrofuran, is stirred at ambient temperature under argon. A solution of 500 mg of 4-nitrophenol in 2 ml of anhydrous tetrahydrofuran is added dropwise at ambient temperature. After stirring for approximately 1 hour at ambient temperature, a solution of 630 mg of methylphenylphosphinic chloride in 2 ml of anhydrous tetrahydrofuran is added dropwise over about ten minutes. After stirring for approximately 2 hours, the reaction medium is diluted with 20 ml of distilled water and the aqueous phase is extracted with 2×20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated under reduced pressure in a rotary evaporator. 995 mg of methylphenylphosphinic acid 4-nitrophenyl ester are obtained with a purity of 50%.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[N:10][O:11][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Product: CC(C)(C)c1ccc(C=NOCc2ccc(CC(=O)O)cc2)cc1

Procedure:
The title compound was prepared as a white solid (0.193 g, 41%) from 4-tert-butyl-benzaldehyde oxime and 4-bromomethyl-phenyl-acetic acid using a procedure similar to example 2. mp=93.3-96.2° C.; mass spectrum (−APCI, M−H) m/z 324. 1H NMR (400 MHz, DMSO-d6); δ 12.30 (bs, 1H), 8.23 (s, 1H), 7.52 (d, 2H), 7.42 (d, 2H), 7.33 (d, 2H), 7.24 (d, 2H), 5.10 (s, 2H), 3.55 (s, 2H), 1.25 (s, 9h). Elemental analysis: Calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30, Found: C, 73.15; H, 7.14; N, 4.01.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>>[CH:23]1([O:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH:14]=[CH:15][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:10][CH:9]=4)[C:12]3=[O:28])=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Product: CNCCOc1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1

Procedure:
1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with methylamine as described in example 6. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+) was obtained in this way.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[N:15]=[C:14]([C:25]([N:27]3[CH2:31][C:30](=[O:32])[NH:29][CH2:28]3)=[O:26])[CH:13]=2)[CH:8]=[C:9]([F:11])[CH:10]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)=O.ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>C(O)=O>[Cl:24][C:19]1[CH:18]=[C:17]([N:16]2[C:12]([C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:10]=[C:9]([F:11])[CH:8]=3)=[CH:13][C:14]([C:25]([N:27]3[CH2:31][C:30](=[O:32])[NH:29][CH2:28]3)=[O:26])=[N:15]2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C1CCNC1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OCCCl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OCCN4CCCC4)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 119A and pyrrolidine without the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 29. 2.5 mg (5% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:12])([C:9]([OH:11])=O)[CH2:5]1)([CH3:3])[CH3:2].[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([C:9]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[O:11])([CH3:12])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC(C)C1CCC(C)(C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C1CCC(C)(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)C1
Temperature: 150 °C
Yield: 42 %

Procedure:
To a stirred solution of 3-isopropyl-1-methylcyclopentanecarboxylic acid (89 mg, 0.52 mmol) and 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (242 mg, 1.04 mmol) in N,N-dimethylformamide (1 mL) was added benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol). The reaction was heated in a microwave at 150° C. for 5 minutes. The reaction mixture was purified with HPLC to yield 1-[(3-isopropyl-1-methylcyclopentyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine in 42% yield (83.3 mg) as off-white solid.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)[CH3:2].[Li+].[CH3:9][C:10]1([C:13]([O:15]C)=O)[CH2:12][CH2:11]1.CC#N>C1COCC1>[CH3:9][C:10]1([C:13](=[O:15])[CH2:2][C:1]#[N:4])[CH2:12][CH2:11]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(C)CC1
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC1(C(=O)CC#N)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine lithium diisopropylamide (LDA, 2.0 M/heptanes; Aldrich; 2.2 eq, 88 mmol, 44 mL) with THF (1.5 mL/mmol; 60 mL) and cool to −78° C. Combine methyl 1-methylcyclopropane carboxylate (TCI US; 4.56 g, 40 mmol) and CH3CN (4.20 mL, 80 mmol) in THF (10 mL) and add slowly with stirring. Stir the mixture at −65 to −78° C. for 1 hour, then remove the bath and warm the mixture to room temperature. Concentrate the reaction mixture to a slurry under reduced pressure. Add hexanes (150 mL) to form a precipitate from the slurry. Collect the solid by vacuum filtration and wash with hexanes (2×50 mL). Replace the catch flask with a clean one, and dissolve the solid on the frit in 50 mL 2.5 M HCl and collect in the flask. Rinse with 20 mL 2.5 M HCl followed by 200 mL Et2O. Separate the layers in the filtrate and extract the acidic phase with Et2O (150 mL). Combine the Et2O organic phases, dry with MgSO4, filter and concentrate under reduced pressure to yield 3-(1-Methyl-cyclopropyl)-3-oxo-propionitrile as a clear amber oil (3.58 g, 29.1 mmol, 73%). Use without purification in reaction with tolylhydrazine hydrochloride (5.23 g, 33.0 mmol) and ethanol (2 mL/mmol) at reflux for 20 hr. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with ethyl acetate (250 mL) and wash with water (2×60 mL), saturated aq. NaHCO3 (60 mL) and saturated aq. sodium chloride (60 mL). Dry the organic phase with MgSO4, filter and concentrate by rotary evaporation. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate and hexane to provide 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (4.2238 g, 18.5 mmol, 46%). LCMS (ES+): m/z=228.2 [M+H].
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:30])[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:28])=[O:29])=[CH:19][CH:20]=2)=[CH:31][CH:32]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(COC(=O)c2ccc(CN3CC(=O)NS3(=O)=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2ccc(C(=O)OCc3ccc(C(=O)O)cc3)cc2)S(=O)(=O)N1
Reaction time: 2 h

Procedure:
The title C compound, 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-t-butoxycarbonyl-benzyl ester (119 mg, 0.19 mmol) is dissolved in CH2Cl2 (5 mL) and then added TFA (5 mL, 64.9 mmol). This is stirred for 2 h and then concentrated under reduced pressure. The residue is suspended in MeCN:water (6:4) (12 mL), centrifuged, decanted and filtered through a 0.1 micron Acrodisc filter. The resulting mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 6 aliquots and eluted at 30 mL/min with a gradient of 90:10 (water containing 0.1% TFA: MeCN) at 0 min to 10:90 at 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated by lyophilization to yield 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-carboxy-benzyl ester as a white amorphous solid: [M−1]−=403.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[CH:13][C:14]([O:41][CH3:42])=[C:15]3[C:19]([C:20](=[O:40])[C:21]([N:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:32]=[N:31][N:30]=5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][NH:17][C:16]=23)[N:10]=1.O.C(O)(C(F)(F)F)=O>>[CH3:42][O:41][C:14]1[CH:13]=[N:12][C:11]([C:9]2[N:10]=[C:6]([CH:2]=[O:1])[S:7][CH:8]=2)=[C:16]2[NH:17][CH:18]=[C:19]([C:20](=[O:40])[C:21](=[O:22])[N:23]3[CH2:24][CH2:25][N:26]([C:29]4[N:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:32]=[N:31][N:30]=4)[CH2:27][CH2:28]3)[C:15]=12
Reactant: COc1cnc(-c2csc(C3OCCO3)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cnc(-c2csc(C=O)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 70 °C
Reaction time: 20 h
Yield: 36.4 %

Procedure:
To a suspension of 1-(7-(2-(1,3-dioxolan-2-yl)thiazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.305 g, 0.519 mmol) in H2O (2 mL, 111 mmol) was added TFA (1 mL, 12.98 mmol). The mixture was heated to 70° C. After 18 h of heating, the mixture was cooled to rt, and was stirred at rt for an additional 20 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was partitioned with sat. NaHCO3. The mixture was extracted with dichloromethane (3×10 mL) and was dried with Na2SO4. The drying agent was removed by filtration. The organic solution was concentrated under reduced pressure, and the resulting mixture was purified by flash chromatography (0 to 5% methanol in dichloromethane gradient). The product, 4-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)thiazole-2-carbaldehyde (0.103 g, 0.189 mmol, 36.5% yield) was collected as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]1[O:32][CH:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=2)[NH2:36])[CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CC(N(C)C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:33]([C:30]3[CH:29]=[C:28]([CH3:27])[O:32][CH:31]=3)[CH:34]=2)=[O:15])=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1cc(-c2cccc(N)c2)co1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mg (2.2 mmol) of (2-[(4-chloro-2-(methoxycarbonyl)phenyl)amino]-2-oxoethoxy)acetic acid was dissolved in 7 mL of THF. 361 mg (2.9 mmol) of oxalyl chloride and a catalytic quantity of DMF were added thereto under ice-cooling, and stirred at room temperature for 2 hours. Thereafter, the solvent was distilled off under reduced pressure. The DMA solution of 380 mg (2.2 mmol) of 3-(5-methylfuran-3-yl)aniline was added to the resulting residue, and stirred for 1 hour. After completion of the reaction, an aqueous sodium bicarbonate solution (was added dropwise, and extraction was carried out using ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give 5-chloro-2-([(2-([3-(5-methylfuran-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 32%).
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH2+:5][CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1>C(#N)C>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:5]1[CH2:6][CH:3]([OH:2])[CH2:4]1)([O-:26])=[O:25]
Reactant: OC1C[NH2+]C1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CN2CC(O)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxyazetidinium chloride (0.68 g, 6.2 mmol) and Hunig's base (2.5 mL, 14.1 mmol) in acetonitrile (10 ml) was added 1-(bromomethyl)-3-nitrobenzene. After the reaction mixture was stirred at room temperature for 18 hours, it was partitioned between ethyl acetate and NaHCO3. The organic layer was washed with brine, dried and concentrated. The crude material was purified by silica gel column chromatography, eluting with 20% ethyl acetate/hexanes to give 0.54 g 1-(3-nitrobenzyl)azetidin-3-ol. MS (DCI(+)) m/e 209 (M+H)+.