Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:34][C:35]1[C:36]2[O:44][CH:43]=[CH:42][C:37]=2[C:38](=[O:41])[NH:39][CH:40]=1.[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][C:46]=1[CH2:55][CH2:56]O>C1COCC1>[Br:34][C:35]1[C:36]2[O:44][CH:43]=[CH:42][C:37]=2[C:38](=[O:41])[N:39]([CH2:56][CH2:55][C:46]2[CH:47]=[CH:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:45]=2)[CH:40]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]cc(Br)c2occc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2ccoc2c(Br)cn1CCc1ccc2ccccc2n1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DIAD (4.91 mmol, 992 mg) was added dropwise to PPh3 (753 mg, 2.80 mmol) in 20 mL of THF. The mixture was stirred for 30 min. Then 7-bromofuro[3,2-c]pyridine-4(5H)-one (300 mg, 1.402 mmol) was added followed by the addition of 2-(quinolin-2-yl)ethanol (243 mg, 1.402 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with water/ethyl acetate. The organic phase was extracted with 1N HCl. The acidic aqueous phase was basified with 1N NaOH and extracted with DCM. The organic phase was extracted with water, dried over MgSO4, filtered, concentrated and purified by chromatography to give the title compound as white solid (119 mg, 23%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]([CH2:25][CH3:26])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:25]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[C:11]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)[CH3:26]
Reactant: CCOC(=O)c1cn(CC)c2cc(C3CCCCC3)c(OC)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(OC)c(C3CCCCC3)cc21

Procedure:
A suspension of 18.7 g of 1-ethyl-4-oxo-6-methoxy-7-cyclohexyl-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester described in Example 18, in 150 ml of ethanol and 150 ml of 2 N sodium hydroxide solution is boiled for 5 hours under reflux. The clear solution thereby produced is evaporated to dryness in vacuo. 2 N Hydrochloric acid is added to the residue. The resulting crystals are filtered off and well washed with water. 1-Ethyl-4-oxo-6-methoxy-7-cyclohexyl-1,4-dihydro-quinoline-3-carboxylic acid, thus obtained, melts at 176°-178°C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:68][O:69][C:70]1[CH:71]=[C:72]([CH:74]=[CH:75][C:76]=1[O:77][CH3:78])[NH2:73]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:68][O:69][C:70]1[CH:71]=[C:72]([NH:73][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:19][C:14]5=[CH:15][N:16]=[CH:17][CH:18]=[C:13]5[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:74]=[CH:75][C:76]=1[O:77][CH3:78]
Reactant: Clc1ccc2ncc(-c3cc4ccncc4s3)n2n1
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5ccncc5s4)n3n2)cc1OC
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.174 mmol, 1.0 equiv), xantphos (20 mg, 0.0349 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0174 mmol, 0.1 equiv), and potassium carbonate (482 mg, 3.49 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (35 mg, 0.227 mmol, 1.3 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 38 mg, of the yellow solid, 54%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35]Br>CN(C=O)C.C(OCC)(=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.00 g) was added to a suspension of sodium hydride (60%, 340 mg) in DMF (5 ml) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, 3,4-difluorobenzyl bromide (1.53 g) was added under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.47 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)([O-:23])=[O:22]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F
Product: O=[N+]([O-])c1ccccc1-c1ccc(S(=O)(=O)NCCCCO)c(C(F)(F)F)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2-nitrophenyl boronic acid were reacted to give the title compound as a thick oil. δC (DMSO, 62.9 MHz): 26.1, 29.5, 42.8, 60.2, 128.2, 124.9, 120.7, 128.7, 130.2, 132.6, 133.1, 133.5, 139.3, 139.8, 141.8 and 147.9.
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][CH:4]([C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCC(N)c1coc([Si](CC)(CC)CC)c1

Procedure:
Reacting 4-(1-hydroxytridecyl)-2-trimethylsilylfuran with diphenylphosphonyl azide and diethyl azidocarboxylate gives 4-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this azide with lithium aluminum hydride gives 4-(1-aminotridecyl)-2-triethylsilylfuran. Acetylation of this intermediate with acetic anhydride gives 4-(1-acetamido)tridecyl-2-triethylsilylfuran. Oxidizing this amide with oxygen using Rose Bengal as an initiator gives 4-(1-acetamido)-5-hydroxy-2(5H)-furanone. Reduction of this furanone with sodium borohydride gives 4-(1-acetamido)-2(5H)-furanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40])[C:33](O)=[O:34])([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([N+:39]([O-:41])=[O:40])=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.16 g of 3,4-dinitrobenzoic acid and 0.76 g of dicyclohexylcarbodiimide are dissolved in 20 ml of methylene chloride, and the solution is stirred at room temperature overnight. After the reaction, the precipitates are collected by filtration. The filtrate is washed with water, dried and then evaporated to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=100:3), whereby 0.8 g of (+)-cis-2-(4-methoxyphenyl)-3-(3,4-dinitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].Cl.[NH2:29][CH2:30][C:31]#[N:32]>>[C:30]([CH2:31][NH:32][C:25]([C:24]1[N:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[C:15]([F:17])[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]=3[C:6]2=[N:5][C:4]=1[C:1]([NH2:2])=[O:3])=[O:26])#[N:29]
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: N#CCN
Agent: Cl
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCC#N

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with aminoacetonitrile hydrochloride similar to as described in Example 2 to afford 9 mg of N3-(cyanomethyl)-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 412 (M)+. 1H NMR (400 MHz, DMSO) δ 12.03 (t, J=5.3 Hz, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.53 (s, 1H), 8.04 (s, 1H), 7.03 (d, J=10.5 Hz, 1H), 5.47 (s, 1H), 5.07-4.90 (m, 2H), 4.66-4.53 (m, 2H), 4.39 (d, J=5.3 Hz, 2H), 1.50 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[C:16]([Cl:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.[F-].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:16]([Cl:21])[N:17]=[C:18]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: OB(O)c1ccsc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(-c3ccsc3)n2)CC1
Temperature: 90 °C

Procedure:
To a solution of 4-(4,6-dichloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (167.1 mg, 0.5 mmol) in anhydrous 1,4-dioxane (4 mL) in an oven-dried flask was added 3-thiopheneboronic acid (70.4 mg, 0.55 mmol), Pd[P(t-Bu)3]2 (2.5 mg, 0.005 mmol), tris(dibenzylideneacetone)-dipalladium(0) (2.3 mg, 0.0025 mmol), and KF (64 mg, 1.1 mmol). The resulting mixture was vacuum flushed with argon and heated overnight at 90° C. The reaction mixture was cooled and passed through a pad of diatomaceous earth, washing with EtOAc. The filtrate was concentrated and the residue was purified by preparative TLC (EtOAc/hexanes, 1:4) to yield a white solid, which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][NH:5][C:4]1=[O:8])[CH3:2].ClC([O:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C.[H-].[Na+]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[CH:6][NH:5][C:4]1=[O:8])[CH3:2].[CH2:1]([CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][C:13]([O-:12])=[O:27])[CH3:2]
Reactant: CCCCCCCCCCCCCC(=O)OC(C)Cl
Agent: CCn1cc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(CC)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
1-Ethyl-4-imidazolin-2-one (1 gm, 0.009 mol) and 1-chloroethyltetradecanoate (2.6 gm, 0.009 mol) were dissolved in 13 ml of dry chloroform and a suspension of sodium hydride in dry benzene (3 ml) was added portionwise. The reaction mixture was stirred at room temperature overnight and was followed by the workup presented in the preceeding examples. After purification by liquid chromatography using silica gel as the supporting material and chloroform as the eluant (EM Silica gel 500 G, 60-200 mesh was used), 1-ethyl-4-imidazolin-2-one-3-α-ethyltetradecanoate was obtained in a yield of 10% (350 mg). 1H n.m.r.(CC14): δ0.90(3H, t, J=5 Hz, CH3 [CH2 ]11CH2 --); 1.28(22H, s, broad, CH3 [CH2 ]11CH2 --); 1.30(3H, t, J=7 Hz, CH3CH2N--); 1.61(3H, d, J=6 Hz, --CHCH3 --); 2.25(2H, t, J=6 Hz, CH3 [CH2 ]10CH2 --); 3.60(2H, q, J=6 Hz, CH3CH2N--); 6.10(1H, d, J=3 Hz, HC=CH); 6.23(1H, d, J=3 Hz, HC=CH); 6.43(1H, q, J=6 Hz, CH3CH--). νmax (film): 3200, 3180(HC=CH), 1745, 1705, 1690(C=O); 1250 cm-1 (C-O-C). m/e+1 367, C21H38N2O3 requires 366.
Reaction SMILES: I[CH3:2].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:36])([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)[C:22]4[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=4)[CH:19]=3)[NH:14][C:13](=[O:37])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1.O>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].[OH-].[Na+].C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:36])([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)[C:22]4[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=4)[CH:19]=3)[N:14]([CH3:2])[C:13](=[O:37])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
BTEAC (0.00395 mol), then iodomethane (0.00474 mol) were added to a solution of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzaldehyde monohydrochloride (described in Example B1) (0.00395 mol) in NaOH (1N) and THF (20 ml). The mixture was stirred at room temperature for 18 hours, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.87 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.61 g (32%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzaldehyde, mp. 208° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCCC1.C(N(CC)CC)C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 90.2 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 20 ml of tetrahydrofuran and 0.5 ml of triethylamine is added a solution of p-toluenesulfonyl chloride (0.95 g, 0.005 mol) in 10 ml of tetrahydrofuran dropwise over a 15 minute period, under nitrogen. After complete addition, the resultant solution is stirred at room temperature for 1 hour. This is quenched in cold water and extracted with methylene chloride (2×, 50 ml). The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a yellow solid. This, after re-crystallization from methanol, gives 2.5 g (90%) of white crystalline 1-[(4-methylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine with melting point 215°-217° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].C1COCC1>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(C2CCc3[nH]c(C(=O)O)cc32)c1
Yield: 44 %

Procedure:
The title compound was synthesized from methyl 4-(3-cyanophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.021 g, 0.079 mmol) and lithium hydroxide (0.035 g, 0.83 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-80% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 8.8 mg (44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21 (dd, J=6.35, 2.34 Hz, 1H), 2.79 (s, 2H), 2.91-3.02 (m, 1H), 4.26 (s, 1H), 6.52 (s, 1H), 7.42-7.48 (m, 1H), 7.49-7.56 (m, 3H); LCMS (ESI−) 251.2 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:6][C:5]=1[F:25].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>ClCCl>[C:15]12([CH2:14][O:13][C:7]3[C:8]([CH:10]([O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:26])=[C:5]([F:25])[CH:6]=3)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl-4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate (0.26 g, 0.72 mmol) and 2,6-lutidine (0.17 mL, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.285 g, 1.08 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. After dilution with dichloromethane (100 mL), the organic phase was washed with 1 N hydrochloric acid (2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo afforded methyl 4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)- oxy)ethyl)-2-fluorobenzoate as a yellowish oil (0.35 g, quant.), which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[N:17][OH:18])[CH:11]=1)[CH3:9])(C)(C)C.[CH3:20][N:21]([CH3:25])[CH2:22][C:23]#[CH:24]>ClCCl>[CH3:20][N:21]([CH2:22][C:23]1[O:18][N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH:24]=1)[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(C=NO)c1
Reactant: C#CCN(C)C
Solvent: ClCCl
Product: C[C@H](N)c1cccc(-c2cc(CN(C)C)on2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of (S)-{1-[3-(hydroxyimino-methyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (260 mg, 1 mmol) in dichloromethane (5 mL) was added dimethylpropargylamine (323 μL, 3 mmol) followed by household bleach (5 mL). The reaction mixture was stirred vigorously at room temperature for 2 h, the two layers were separated, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, the crude product was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by solid phase extraction (SCX cartridge, silica gel benzene sulfonic acid linked) to give the title product (200 mg, 82% yield) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[N:21]1[S:22][N:23]=[C:24]2[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=12>>[N:21]1[S:22][N:23]=[C:24]2[C:29]([S:30]([N:8]3[C:9]4[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=12
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc3nsnc23)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
To a solution of 1-(5-methoxy-11H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,1,3-benzothiadiazole-4-sulfonyl chloride (26 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 11%) as a yellow solid. MS (ESI+) for C18H18N4O3S2 m/z 403 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1([S:18](Cl)(=[O:20])=[O:19])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>C1COCC1>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[S:18]([CH:15]1[CH2:17][CH2:16]1)(=[O:20])=[O:19]
Reactant: CN[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN([C@@H]1CCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (100 mg, 0.5 mmol) in 2.5 mL THF was added cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) and DIPEA (0.10 mL, 0.60 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight. Water was added, and then extracted with EtOAc. The organic layers were combined washed with brine, dried over Na2SO4, and evaporated in vacuo to afford the crude title product which was used for the next step without further purification. MS (m/z): 305 (M+H)+.