Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[C:4]([CH2:6][C:7]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19]C)=[O:18])=[N:15][CH:16]=2)[CH2:8]1)#[N:5].Cl>CO.O>[C:4]([CH2:6][C:7]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=2)[CH2:8]1)#[N:5]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)nc5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of lithium hydroxide monohydrate (0.87 g, 21 mmol) and methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylate (3.70 g, 6.79 mmol) in methanol (10.0 mL) and water (5.0 mL) was stirred at room temperature overnight. The mixture was adjusted to pH 3 with aqueous HCl (1.0 N), and concentrated under reduced pressure to remove methanol. The solid formed was filtered and washed with water, and dried under reduced pressure to afford the crude product. LCMS (M+H)+: m/z=531.1.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])([C:18]([F:19])([F:20])[F:21])[C:11]([O:13][CH3:3])=[O:12])=[CH:22][CH:23]=1
Reactant: O=C(O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
An excess of a solution of diazomethane in ether is added to an ethereal solution of 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid (0.25 g.) at 0° C. Evaporation of the resulting solution yields methyl 2(4chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (0.25 g.), b.p. (bath temperature) 140° C. at 30 mm. pressure.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[BH3-]C#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCNCC1CCCCC1

Procedure:
To 100 mL of MeOH is added 2-propenylamine (5.7 g, 0.1 mol), 11.2 g (0.1 mol) of cyclohexane carboxaldehyde and 12 g (0.2 mol) of NaBH3CN. The pH is adjusted to 6 with concentrated HCl. Monitor the reaction by thin layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of Et2O. Add 1N NaOH to the aqueous solution until it is basic (pH=11) and extract 2 times with 200 mL of Et2O. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27].O.NN>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26]([NH:7][NH2:8])=[O:27]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CC#N
Solvent: O
Product: NNC(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were added to a suspension of 2-chloro-isonicotinic acid (800 mg, 5.08 mmol) in acetonitrile (10.3 ml) at room temperature. After two h a solution of hydrazine monohydrate (0.493 ml, 10.2 mmol) in acetonitrile (5.0 ml) was added drop-wise at 0° C. After 30 min, the solvent was removed using a roto-evaporator and the residue was diluted with ethyl acetate, quenched with water, dried over sodium sulfate, filtered and concentrated to afford 2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid). 1H NMR (DMSO) d (ppm): 10.21 (bs, 1H), 8.55 (d, 1H), 7.82 (s, 1H), 7.75 (d, 1H), 4.69 (bs, 2H).
Reaction SMILES: N.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[O:16][C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[O:18])=[N:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C>[NH2:38][C:33](=[O:35])[CH2:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]([C:15]3[O:16][C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=4)=[N:13][N:14]=3)=[O:18])=[CH:21][CH:22]=2)[CH2:31][CH2:30]1
Reactant: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)o2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(N)=O)CC4)cc3)o2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Ammonia (0.06 mL of a 28-30% wt % solution in water) was added to a stirred mixture of (trans-4-{4-[({5-[(3-ethoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Example 113, 65 mg), EDAC (32 mg), and HOBt (23 mg) in DMF (1 mL). The mixture was stirred for 16 h then was diluted with DMF (2 mL) and heated to 100° C. for 30 minutes in an Emrys Optimizer™ microwave. The crude mixture was purified directly by HPLC using a gradient of 25-75% acetonitrile/water with 1% ammonia as the eluent to give the title compound (10 mg) as a solid; 1H NMR δ 10.82 (2H, bs), 7.68 (2H, d), 7.22 (5H, m), 7.08 (1H, 1H), 6.67 (1H, s), 6.56 (1H, m), 4.00 (2H, quartet), 2.50 (1H+ DMSO, m), 1.96 (2H, d), 1.83-1.66 (5H, m), 1.42 (2H, m), 1.33(3H, t), 1.08 (2H, m); MS m/e MH+ 474.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:30])[NH:24][C:25]([CH3:29])=[N:26]2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:28]=[C:27]4[C:22]([C:23](=[O:30])[NH:24][C:25]([CH3:29])=[N:26]4)=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Sc1cccc2cnccc12
Reactant: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 150 mg (0.9 mmol), DMF 5 ml, potassium carbonate 250 mg (1.8 mmol) and 7-chloro-2-methyl-6-nitro-3,4-dihydro-4-quinazolinone 200 mg (0.8 mmol) was stirred at room temperature for 2 hours, and 7-(5-isoquinolylsulfanyl)-2-methyl-6-nitro-3,4-dihydro-4-quinazolinone 260 mg (83.7%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: CI
Reactant: Cc1c(Br)cnc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cn(C)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 5-bromo-4-methyl-3-nitropyridin-2-ol (15.00 g, 64.37 mmol) [Combi-Blocks, AN-1086] in N,N-dimethylformamide (250 mL) was treated with sodium hydride (3.09 g, 77.3 mmol) (60% dispersion on mineral oil) slowly and portionwise, and stirred at RT for 30 min. The reaction mixture was treated with methyl iodide (4.81 mL, 77.2 mmol) dropwise and stirred at RT for 3 h. LCMS indicated a clean peak for methylated product. The reaction mixture was poured over water/ice (˜400 mL) and allowed to stir while the ice melted. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (14.9 g, 93%) that was used without further purification. LCMS calculated for C7H8BrN2O3 (M+H)+: m/z=247.0, 249.0. found: 247.0, 248.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:31]=[CH:32][N:28]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][O:22]4)[N:29]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccn(C2CCCCO2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(C4CCCCO4)n3)c3cc(Br)cnc32)cc1

Procedure:
Using the same reaction conditions as described in step-i of example 1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (100 mg, 0.209 mmol) was coupled with (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (103 mg, 0.524 mmol) using sodium carbonate (66 mg, 0.627 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.0104 mmol) in DME/water (3/0.7 ml) to afford 60 mg (crude) product. MS: m/z=501.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCC(C)C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 70.4 %

Procedure:
5-methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL, 43.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 14.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 46. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 6.6035 g (70.3%) of 46. 1H (CDCl3, 400 MHz): δ 6.28 (1H, s), 4.25 (2H, q, J=7.0 Hz), 2.40 (2H, t, 7.6 Hz), 1.54-1.41 (3H, m), 1.27 (3H, t, J=7.3 Hz), 0.82 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 203.40, 166.27, 161.85, 101.37, 62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 21.99, 13.77; CH2 carbons: 62.15, 38.74, 33.39; CH carbons: 101.37, 27.46 ppm. HPLC: 11.038min.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[CH2:21]([O:23][C:24]1[C:25]([C:36](=O)[CH3:37])=[CH:26][C:27]2[CH:28]=[CH:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)[CH3:22]>C1COCC1>[CH2:21]([O:23][C:24]1[C:25](/[C:36](/[CH3:37])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:26][C:27]2[CH:28]=[CH:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)[CH3:22]
Reactant: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triethyl 2-fluoro-2-phosphonoacetate (0.61 g, 2.50 mmol) in THF (5 mL) at −78° C. was added n-butyllithium (1.6 M in hexane, 1.6 mL, 2.5 mmol). After 10 min, a solution of 1-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-25, 122 mg, 0.50 mmol) in THF (2 mL) was added and the reaction was stirred for 6 b while warming gradually to room temperature. The reaction was then quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCOCCOc1cc2ncnc(Oc3ccc4cccnc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (200 mg, 0.64 mmol), potassium carbonate (102 mg, 0.74 mmol) and 7-hydroxyquinoline (107 mg, 0.74 mmol) in DMSO (5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The mixture was poured into water, washed with dichloromethane and extracted twice with a 10/1 mixture of dichloromethane/methanol. The extracts were washed with water and brine, dried over magnesium sulphate, filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography, eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give an oil which crystallised on trituration with ether to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline (148 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[O:14].F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N-]>ClCCl>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[CH:8]3[CH2:7][CH:6]([CH2:13]3)[C:5](=[O:14])[CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]=2[CH:3]=1
Reactant: O=C1c2cc(Br)c(F)cc2C2CC1C2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C2CC(C2)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 6-bromo-7-fluoro-2,3-dihydro-1,3-methanonaphthalen-4(1H)-one (9.00 g, 35.3 mmol) in dry dichloromethane (180 mL) at 0° C. was introduced triethyloxonium tetrafluoroborate (141 mL of a 1.0M solution in dichloromethane, 141 mmol) dropwise over 15 minutes. A solution of ethyl diazoacetate (8.05 g in 75 mL dry dichloromethane, 70.6 mmol) was then added slowly over 20 minutes ensuring the reaction temperature did not rise >3° C. After 30 minutes, the reaction mixture was allowed to warm to room temperature for 16 hr. The solution was then re-cooled to 0° C. and re-treated with triethyloxonium tetrafluoroborate (141 mL of a 1.0M solution in dichloromethane, 141 mmol) and ethyl diazoacetate (8.05 g in 75 mL dry dichloromethane, 70.6 mmol) as described for the first treatment. After warming to room temperature for 5½ hours, the reaction mixture was washed with saturated aqueous sodium bicarbonate (3×100 mL washes), the organic phase dried over sodium sulfate and filtered under vacuum through a Celite 0 pad. The filtrate was adsorbed onto silica gel in vacuo and purified by silica gel flash column chromatography (heptanes/ethyl acetate gradient elution of increasing polarity) to furnish the title compound (8.70 g, 25.50 mmol, 72%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J=7.09 Hz, 4H) 1.84 (dd, J=11.66, 6.62 Hz, 1H) 2.32 (dd, J=12.93, 6.94 Hz, 1H) 2.80 (dt, J=12.61, 7.88 Hz, 1H) 3.04 (dt, J=11.90, 8.55 Hz, 1H) 3.38 (ddd, J=8.83, 7.57, 3.78 Hz, 1H) 3.45 (td, J=8.20, 3.78 Hz, 1H) 4.18-4.29 (m, 2H) 4.78 (s, 1H) 6.88 (d, J=9.14 Hz, 1H) 7.48 (d, J=6.94 Hz, 1H); M+23=363/365.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=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.[I:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45]2)=[CH:40][CH:39]=1.O>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][CH2:49][C:46]2[CH:47]=[CH:48][N:44]([C:41]3[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=3)[CH:45]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccn(-c2ccc(I)cc2)c1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (60 mg, 0.37 mmol) and TEA (0.102 mL, 0.73 mmol) in DMF (4 mL) was added BOP (196 mg, 0.44 mmol). After 10 min of stirring, the solution was added to a sample of (1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg, 0.31 mmol) in a flask. The mixture was stirred at room temperature overnight. H2O was added to induce precipitation. The resulting precipitate was collected and dried on vacuum to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide (118 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: O=C1CCN(Cc2ccccn2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccccn2)CC1

Procedure:
1-(2-Pyridinylmethyl)-4-piperidone oxime is prepared from 1-(2-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Reaction time: 8 h

Procedure:
All 11 ml (33 g.) of bromine to a mixture of ethyl 5-chloro-3-phenylindole-2-carboxylate (30 g.) in 100 ml of acetic acid at 10- 20°. Stir overnight and then add a solution of sodium bisulfite. Filter and wash the precipitate with water. Stir the solid with methanol and filter to yield the title compound. Recrystallization from methanol yields the analytical sample; m.p. 205°-206°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)#[CH:14]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[O:11][N:10]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2cc(-c3c(Cl)cccc3Cl)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.67 g, 11.9 mmol) and 4-ethynylbenzonitrile (1.50 g, 11.9 mmol) were dissolved in anhydrous tetrahydrofuran (150 mL) and triethylamine (2.15 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 6 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 4-ethynylbenzonitrile. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 7:3 hexanes-ethyl acetate. The appropriate fractions were combined to give 3-(2,6-dichlorophenyl)-5-(4-cyanophenyl) isoxazole as a white solid, 0.58 g.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.CS([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)(=O)=O.[N-]=C=O.ClC1C=CC(CC2CC3N(CC(N)C)C(CC3)C2)=CC=1>C(Cl)Cl>[CH:22]12[CH2:23][CH2:18][CH:19]([CH:5]([OH:11])[CH2:21]1)[CH2:20][NH:24]2
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CC(N)CN1C2CCC1CC(Cc1ccc(Cl)cc1)C2
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Product: OC1CC2CCC1CN2
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To a solution of triphosgene (0.22 g, 0.33 eq.) in CH2Cl2 was added 3-methane-sulfonyl-phenylamine hydrochloride (0.5 g, 2.4 mmol), followed by the dropwise addition of TEA (0.37 ml, 1.1 eq.). The mixture was heated to 40° C. for 30 min. It was allowed to cool to rt and stirred for an additional 45 min. The isocyanate solution was then added to a solution of 2-[3-(4-chlorobenzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methyl-ethylamine (0.18 g, 0.6 mmol) (prepared according to the procedure described in example 4, steps 1 to 4) in 6 ml of CH2Cl2. The mixture was stirred overnight at rt. It was diluted with CH2Cl2 and the organic layer was washed with Na2CO3 (sat.) twice, NaCl (sat.) and dried over Na2SO4. The crude mixture was purified on a silica-gel column with 1% iPrNH2, 9% MeOH in EtOAc to give 55% of Example 5 (M+: 490).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([OH:40])=O)[CH:32]=[CH:33][C:34]=1[S:35][CH3:36].C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:40])[CH:32]=[CH:33][C:34]=1[S:35][CH3:36]
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A solution of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.41 mmol) and 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29 g, 0.95 mmol) in methylene chloride (10 mL) was treated with N,N-diisopropylethylamine (500 μL, 2.87 mmol) and 2-aminothiazole (140 mg, 1.27 mmol). The mixture was stirred under nitrogen at 25° C. for 14 h. The reaction mixture was then washed with a 6N aqueous hydrochloric acid solution (1×15 mL) and washed with a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for C18H21ClN2OS2 (M+) 380.0783, found 380.0792.