Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)[C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([S:25][CH3:24])[CH:27]=2)=[O:34])=[CH:8][CH:9]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: COC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(CN(C(=O)Nc2cccc(SC)c2)C2CCC3(CCCCC3)CC2)cc1
Reaction time: 48 h
Yield: 44.2 %

Procedure:
The above 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester (1.02 g, 3.2 mmol) was added acetonitrile (50 mL) and 3-(methylthio)phenylisocyanate (668 mg, 4 mmol). Upon stirring for 2 days, the reaction appeared incomplete as shown by HPLC, so another portion of 3-(methylthio)phenylisocyanate (240 mg) was added. After stirring for 2 hours the solvent was evaporated. The residue was taken up in dichloromethane (2 mL) and purified by chromatography on silica using dichloromethane as eluent affording 4-[3-(3-methylsulfanylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (680 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:58]=[CH:57][C:52]([O:53][CH2:54][CH2:55][OH:56])=[CH:51][C:50]=1[O:59][CH3:60]>CN(C=O)C>[OH:56][CH2:55][CH2:54][O:53][C:52]1[CH:57]=[CH:58][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:59][CH3:60])[CH:51]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: COc1cc(OCCO)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCO)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.8 mg, 0.035 mmol), TBTU (11.2 mg, 0.035 mmol) and ethyl-diisopropylamine (18.0 μL, 0.105 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to 2-(4-aminomethyl-3-methoxy-phenoxy)-ethanol (6.4 mg, 0.035 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless lyophilisate. LC-MS: tR=0.98 min, [M+1]+=402.16.
Reaction SMILES: [Na].[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([O:19]CC)=[O:18]>C(O)C>[C:22]1([CH:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:13][CH:12]=2)[C:17]([OH:19])=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc(N2CCCCC2)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=C(O)C(Oc1ccc(N2CCCCC2)cc1)c1ccccc1

Procedure:
2.3 g. of sodium is dissolved in 100 ml. of absolute ethanol; 17.7 g. of 4-piperidinophenol is introduced into the solution, and then 24.3 g. of ethyl α-bromophenylacetate is added dropwise thereto and the mixture refluxed for 10 hours. The reaction mixture is then evaporated, the residue mixed with water, and the aqueous solution extracted with ethyl acetate. The ethyl acetate solution is washed twice with dilute KOH and twice with water, then dried, and the solvent is evaporated, thus obtaining the ethyl ester of α-phenyl-α-4-piperidinophenoxy-acetic acid; hydrochloride, m.p. 149°-151°.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccnc1
Product: CC(C)(C)c1cc(N)n(-c2cccnc2)n1
Yield: 77.3 %

Procedure:
Following the procedure in Example 161A Step 3, 3-hydrazinylpyridine (501 mg, 4.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (437 mg, 4.0 mmol) were reacted to give 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (667 mg, 3.09 mmol, 77%), LC-MS (ESI) m/z 217 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[CH:19]=[C:18]([Cl:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:19]=[C:18]([Cl:25])[CH:17]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1cc(NN)nc2c(C)cccc12
Product: Cc1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2c(C)cccc12

Procedure:
A solution of 2-hydrazinyl-4,8-dimethylquinoline (100 mg, 0.53 mmol) and 100 mg (1.0 eq) of 1,3-dichloro-5-isocyanatobenzene was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H) 2.55 (s, 3 H) 6.77-6.80 (m, 1 H) 7.09 (t, J=1.76 Hz, 1 H) 7.17 (dd, J=8.20, 7.03 Hz, 1 H) 7.40 (d, J=6.74 Hz, 1 H) 7.65-7.72 (m, 3 H) 8.40 (br. s., 1 H) 8.62 (s, 1 H) 9.25 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:36]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc5ccccc45)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg) was dissolved in chloroform (10 ml), and 1-naphthyl isocyanate (75 mg) was added to the solution. The mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal. The crystal was collected by filtration to give 105 mg (yield 57%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:33][OH:34].[K+].[Br-]>>[OH:34][NH:33][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NO
Reactant: CCCCCC#CCC(CC#CCCCCC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCCC#CCC(CC#CCCCCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 62 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g of the product isolated. Yield 62%; white solid; mp 83-84° C.; 462.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0 Hz, 2H), 3.00 (brd, J=17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s;
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH3:16].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 85.3 %

Procedure:
Ferulic acid (4.85 g) and then ethyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for 2.5 hours. The disappearance of the starting material was confirmed by TLC (n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the wine-colored crude product (5.79 g). The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=3/1) to obtain the above-identified compound (5.06 g; 91.2%). The product was crystallized from n-hexane to obtain a white crystal (4.743 g, 85.3%). Melting point: 41°-43° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38]Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)N(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Using General Procedure A, [4-(1-pyridin-2-ylethylamino)-butyl]-carbamic acid tert-butyl ester, N-(t-butoxycarbonyl)-2-chloromethylbenzimidazole, and KI in anhydrous CH3CN were reacted with DIPEA to obtain 2-{[(4-tert-butoxycarbonylaminobutyl)-(1-pyridin-2-ylethyl)-amino]-methyl}benzimidazole-1-carboxylic acid tert-butyl ester. Conversion to the HBr salt gave COMPOUND 219 as a white solid. 1H NMR (D2O) δ 1.55 (br, 4H), 1.63 (d, 3H, 6.9 Hz), 2.62 (m, 1H), 2.80 (m, 1H), 2.88 (br, 2H), 4.43 (d, 2H, J=2.4 Hz), 4.58 (m, 1H), 7.60 (m, 2H), 7.78 (m, 2H), 7.97 (t, 1H, J=6.6 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.56 (t, 1H, J=8.0 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 13.17, 24.44, 24.97, 39.57, 47.46, 52.31, 59.31, 114.26 (2C), 126.57, 126.74, 126.92 (2C), 130.92 (2C), 141.83, 148.12, 152.04, 156.52. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.3.1HBr.1.8H2O.0.2C4H10O: C, 38.26; H, 5.47; N, 11.27; Br, 39.85. Found: C, 38.22; H, 5.13; N, 11.16; Br, 40.00.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:22]([O:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: O=C1CCc2cc(C(=O)N3CCC(=NO)CC3)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 Grams of 6-(4-hydroxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril, 11.4 ml of acetic anhydride and 31.8 ml of triethylamine in 300 ml of methylene chloride solution were mixed together and stirred at room temperature overnight. The reaction mixture was poured into ice-water, and extracted with chloroform. The chloroform extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation to yield 16.5 g of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([F:12])[CH:3]=1.[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19]>O1CCOCC1>[F:12][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C:15]2=[O:19])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:11]
Reactant: O=C1NCC[C@@H]1O
Reactant: O=C1CCc2c(F)cc(Br)cc21
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-4-fluoro-indan-1-one (Enamine, 453 mg), (S)-3-hydroxy-pyrrolidin-2-one (200 mg) and 1,4-dioxane (3 mL) was purged with argon. Cesium carbonate (645 mg), N,N′-dimethyl-ethylene-diamine (2.24 mL) and copper(I) iodide (38 mg) were added and the mixture was heated to 80° C. for 3 hours. After cooling to r.t. the mixture was filtered and the filtrate evaporated. The residue was purified by SGC (eluent: heptane/EA 1:1 with 0 to 20% MeOH) to provide the title compound. MS ESI+: m/z=250 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21]([NH:30][CH3:29])=[O:23])=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(=O)O)n3)nc2N1C1CCCC1
Reactant: CN
Agent: Cl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(=O)NC)n3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-3-carboxylic acid (Example 56) used instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44) and methylamine hydrochloride instead of dimethylamine hydrochloride. LCMS: 384.2 m/z (M+H)+; ret. Time: 3.65 min (Analytical Method A).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(C)=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
457 g of methanesulfonyl chloride was added dropwise to a solution of 1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester, 435 g of triethylamine and 1.9 L of chloroform at not higher than 15° C. while cooling. After stirring for 30 minutes, 1N hydrochloric acid (0.6 L) was added, and the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate (600 g), washed with water (0.6 L), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester as an oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].Cl>C(Cl)Cl>[CH3:16][C:15]([C:11]1[CH:12]=[C:13]([C:1](=[O:3])[CH3:2])[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]=1[OH:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -4 °C

Procedure:
Under a nitrogen atmosphere, 6.89 ml of acetylchloride and 14.75 ml of stannic chloride were dissolved in 200 ml of methylene chloride and chilled to -4° C. To this was added 20 g of 2,6-di-t-butylphenol (in 100 ml of methylene chloride) over 10 minutes. The resultant mixture was stirred for 30 minutes at 0° C., then poured into a mixture of 400 ml of ice and 1N hydrochloric acid and stirred. The mixture separated into layers which were subsequently separated. The organic layer was washed with 100 ml of saturated sodium bicarbonate and 100 ml of brine. The organic layer was dried and the solvent evaporated to give 23.39 g of the desired subtitled intermediate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=1.CN1C=CN=C1.[F:27][CH:28]([F:33])[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:27][CH:28]([F:33])[S:29]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH:7]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=2)[C:8]1=[O:11])(=[O:31])=[O:30]
Reactant: COc1nc(C)nc(C2C(=O)Nc3c(F)cccc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1nc(C)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
7-Fluoro-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (1.20 g) and 1-methyl-1H-imidazole (0.97 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (1.21 g) is added in 2 portions and the mixture is warmed to room temperature. After 5 hours, 1-methyl-1H-imidazole (0.32 g) and difluoromethanesulfonyl chloride (0.61 g) are added and the mixture is stirred for 16 hours. After adding water and some hydrochloric acid, the solid is filtered off, washed with dichloromethane and water and dried. This gives the title compound as a solid in an HPLC purity of 91% (1.54 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C=O)C.O>[Cl:5][CH2:4][CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-bromo-3-chloropropane (3.4 mL, 34.5 mmol) in DMF (40 mL), was added potassium carbonate (6.4 g, 69 mmol) and morpholine (2.0 mL, 23.0 mmol). The solution was stirred at RT for 15 h, then diluted with H2O (150 mL). The mixture was extracted with EtOAc (3×25 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give title compound as a colorless oil. MS (ESI, pos. ion) m/z: 164 (M+1). Mass Calc'd for C7H14ClNO: 163.08.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.[CH3:17][NH:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:18]([CH3:17])[N:19]=1
Reactant: CNN
Reactant: COc1ccccc1C(=O)c1sccc1Br
Solvent: OCCO
Product: COc1ccccc1-c1nn(C)c2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-bromothien-2-yl) (2-methoxyphenyl)methanone (10 g), methyl hydrazine (10 ml) and ethylene glycol (70 ml) was stirred at 110°-120° C. for two hours under nitrogen. The reaction mixture was then allowed to cool to room temperature, quenched with 125 ml of water and the organics were extracted into a 50:50 ether/ethyl acetate solution. Washing, drying (over anhydrous magnesium sulfate) and then evaporation of the solvents left 10 g of an oil. This oil was passed through a silica gel column packed in hexane and eluted with dichloromethane to give 7 g of an oil which subsequently crystallized. Recrystallization from ether/hexane gave 4 g of a crystalline solid, m.p. 94°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][CH2:27][NH2:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH3:13])[C:9]=1[C:10](=[O:12])[NH:28][CH2:27][CH2:26][C:18]1[N:17]([CH3:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)=[O:4]
Reactant: Cn1c(CCN)nc2ccccc21
Reactant: COC(=O)c1ncn(C)c1C(=O)O
Agent: Cl
Product: COC(=O)c1ncn(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 1-methyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (200 mg, 1.09 mmol) and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (296 mg, 1.19 mmol) according to the method described in example 8, step 3 as pink foam (156 mg, 457 μmol, 42.1%). MS: M=342.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[OH-].[Na+]>CO>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1/[CH:15]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Commercially available 5-acetylthiophene-2-carboxylic acid (1.0 g, 5.9 mmol) and commercially available 2-chlorobenzaldehyde (670 uL, 5.9 mmol) were dissolved in 30 mL of methanol. The solution was cooled in an ice bath and solid sodium hydroxide (940 mg, 23.5 mmol) was added. The cold bath was removed and the reaction was stirred for 2 hours at room temperature. The reaction was then heated at 50° C. for another 2 hours. Concentrated HCl was added to lower the pH to 3. The reaction was filtered, washed with water and air dried to give 1.5 g of product. MS (EI) for C14H9ClO3S: 292 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[F:24][C:25]([F:33])([F:32])[CH2:26][NH:27][C:28]([NH:30][NH2:31])=S.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:13][C:28]([NH:27][CH2:26][C:25]([F:33])([F:32])[F:24])=[N:30][N:31]=3)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=2)(=[O:15])=[O:16])[CH:3]=1
Reactant: NNC(=S)NCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.1 %

Procedure:
A solution of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.996 g, 4.52 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarbothioamide (0.783 g, 4.52 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.60 g, 13.57 mmol) (Sigma-Aldrich) in DMF (8.0 mL) was heated at 80° C. for 21.25 h, then at 90° C. for 24 h. The solution was cooled to RT. H2O was added and the solution was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude material. The crude material was purified by flash chromatography (10-60% EtOAc in Hex). The fractions were combined and DCM was added to the residue. A solid was present and was removed by filtration to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (180 mg, 0.320 mmol, 7.08%) as an off white solid. MS (ESI, pos. ion) m/z: 562.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (t, J=6.6 Hz, 1H), 8.21 (s, 1H), 8.10-8.16 (m, 1H), 7.89-7.99 (m, 3H), 7.73 (s, 1H), 7.43 (d, J=8.2 Hz, 2H), 4.06-4.20 (m, 2H), 2.33 (s, 3H).