Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]=[C:54]=[O:55])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[NH:53][C:54]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:55])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)Nc3ccccc3Oc3ccccc3)CN2C1=O
Yield: 15.3 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-phenoxyphenyl isocyanate (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 21 mg (15%) of 18-(2-phenoxyphenylaminocarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.2% pure (HPLC), MS m/z 780 (M−H)−, HRMS: calcd. 799.3337 and found 799.3325 (M+NH4)−, mp 151-153° C.
Reaction SMILES: [F-:1].[F-:2].[F-].C(N(SN(CC)CC)CC)C.[C:15]([O:18][CH2:19][C:20]1[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:15]([O:18][CH2:19][C:20]1[O:24][C:23]([CH:25]([F:2])[F:1])=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1ccc(C=O)o1
Reactant: [F-]
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(F)F)o1
Temperature: 20 °C

Procedure:
A solution containing 7.26 cm3 of DAST (diethylamino sulphide trifluoride) and 30 cm3 of methylene chloride is added at 5° C. to a solution containing 10 g of the product prepared in Stage A and 100 cm3 of methylene chloride. The reaction mixture is agitated at 20° C. for half an hour and is taken to reflux for 1 hour. It is maintained under agitation for 18 hours at 20° C. and taken to reflux for 3 hours, then treated with sodium acid carbonate and extracted with methylene chloride. After drying and concentrating, 12 g of a product is obtained which is chromatographed on silica eluting with a hexane--ethyl acetate mixture (8-2). In this way 5.5 g of desired product is obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH2:29][O:30][C:31]([N:33]2[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[NH:34]2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (3.24 g, 10.55 mmol) in DMF (30 mL) was added 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.2 g, 8.79 mmol) followed by DIPEA (3.07 mL, 17.58 mmol). The reaction was stirred at 25° C. for 18 hrs. The reaction was concentrated and purified by reverse-phase HPLC to afford 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid as a mixture of diastereomers. LC-MS (ES) m/e 538.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>C(N(CC)CC)C.[Cu]I.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>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 14271.2 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynylbenzene (1.53 g, 0.015 mol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2Cl2 (210 mg, 0.2 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 4-nitro-2-(phenylethynyl)aniline (340 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 4.95 (brs, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(O)=O.BrC1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1.BrC1C=NC=CC=1>>[C:4]1([C:1]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: Brc1cccnc1
Product: O=C(O)c1ccc(-c2ccccc2)s1

Procedure:
Following the procedure of Preparation 1(a), except substituting phenylboronic acid for 4-carboxybenzeneboronic acid and 5-bromo-2-thiophenecarboxylic acid for 3-bromopyridine, afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([NH:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CNc2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 200 °C
Yield: 63 %

Procedure:
A mixture of 5-bromo-2-chloro-1H-benzoimidazole (0.100 g, 0.432 mmol) and 4-trifluoromethyl-benzylamine (0.8 mL) was heated in a microwave apparatus at 200° C. for 1 hour. The reaction mixture was cooled, and purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title product as a white solid (0.101 g, 63%).
Reaction SMILES: [F:1][B-](F)(F)F.[H+].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)N)([CH3:10])([CH3:9])[CH3:8].N([O-])=O.[Na+]>O>[C:7]([C:11]1[CH:17]=[CH:16][CH:15]=[C:13]([F:1])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)c1cccc(N)c1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88956.8 %

Procedure:
To a vigorously stirred solution of tetrafluoroboric acid (73.26 mL; 0.4 mol; 48% wt % solution in water) in a large beaker at room temperature was slowly added 3-tert-butylaniline (15.0 g; 0.10 mmol). The resulting mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and then a solution of sodium nitrite (11.09 g; 0.16 mol) in water (30 mL) was added. After addition was complete reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature and further stirred for 20 minutes. The resulting beige slushy material was filtered, washed with tetrafluoroboric acid (20 mL) and ether (3×20 mL) to yield an off-white solid (13.54 g). The latter was dissolved in dichloromethane (300 mL) and heated at reflux for 2 hours until the solid was dissolved and no more gas (HF) evolution was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield a dark oil that was purified by column chromatography eluting with ethyl acetate/hexanes (0 to 5% v/v gradient elution over 1 L) to yield the title compound as a pale yellow liquid (11.80 g).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccccc3N(C)c3cscc32)CC1

Procedure:
A solution of 1.2 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 6 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentratedto dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled, and made alkaline with concentrated ammonium hydroxide solution. The precipitate is collected, washed with water and dissolved in chloroform. The chloroform solution is dried and concentrated to an oil, which slowly crystallizes. Recrystallization from ethanol gives yellow crystals, m.p. 83°-85° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([CH:30]=1)C(Cl)=O>C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:30]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1OC1CC1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
Acetonitrile (200 mL) was added to potassium 3-ethoxy-3-oxopropanoate (31.1 g, 182.7 mmol), in a 1000 mL 3-necked flask under N2 with stirring. The reaction mixture was cooled to 0° C., then triethylamine (38.8 mL, 278.4 mmol) was added, followed by MgCl2 (20.71 g, 217.5 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 2.5 h. The resulting slurry was cooled to 0° C. and 5-chloro-2-cyclopropoxybenzoyl chloride (18.5 g, 87 mmol) was added dropwise followed by the addition of more triethylamine (3.9 mL, 28 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo. 1 L of toluene was added, the mixture was cooled to 0° C., then 125 mL of HCl (13% aqueous solution) was added. The ice bath was removed, the mixture was stirred for 30 minutes, then the layers were separated and the organics washed with water and evaporated to dryness. The residue was purified by silica gel chromatography (Hexanes/EtOAc=3:1) to afford 21.8 g of ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=283.0; 1H NMR (400 MHz, CDCl3) δ: 7.81 (t, 1H), 7.44 (dd, 1H), 7.29 (d, 1H), 4.24 (m, 2H), 3.87 (s, 2H), 3.78 (m, 1H), 1.23 (t, 2H), 0.85 (m, 4H).
Reaction SMILES: C([N:11]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28])(OCC1C=CC=CC=1)=O.[CH2:38]([N:40](CC)[CH2:41][CH3:42])[CH3:39].N1CCCC1>CCOCC>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:40]2[CH2:41][CH2:42][CH2:39][CH2:38]2)=[O:34])=[CH:36][CH:37]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCNC1
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCC1

Procedure:
A solution of 6.0 g. of 4-[N-carbobenzyloxy-N-(16-bromohexadecyl)amino]benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 1.1 g. of pyrrolidine. After 1 hour at reflux, the precipitate is filtered off and washed with warm ether. After evaporation in dryness, the intermediate is dissolved in 50 ml. 30% hydrobromic/acetic acid and warmed at 50° for 2 hours. The solvents are evaporated and the product is partitioned between methylene chloride and water. The layers are separated and the methylene chloride is evaporated. The residue is crystallized from acetone to yield colorless crystals.
Reaction SMILES: [C:1]([C@H:4]1[C@H:9]2[CH2:10][C@H:6]([CH:7]=[CH:8]2)[C@H:5]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]2[NH:19][C:20]([C:22]3[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=3)[C:25]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[O:26])=[N:21][C:13]=12)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:18][C:17]1[C:12]([NH:11][C@@H:5]2[C@@H:6]3[CH2:10][C@@H:9]([CH:8]=[CH:7]3)[C@@H:4]2[C:1]([NH2:2])=[O:3])=[C:13]2[N:21]=[C:20]([C:22]3[CH:42]=[CH:41][CH:40]=[C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])[CH:23]=3)[NH:19][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(C(=O)N5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
tert-butyl 4-(3-(7-((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-ylamino)-6-chloro-3H-imidazo[4,5-b]pyridine-2-yl)benzoyl)piperazine-1-carboxylate (18) (160 mg, 0.27 mmol) was dissolved in 2 mL of 20% TFA solution in DCM. The reaction mixture was stirred at room temperature for 6 h. After 6 h, DCM was evaporated and the residue was triturated with ether to obtain the desired product (75 mg, 56% yield) as a light brown hygroscopic solid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC1CCCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC1CCCCN1c1ccc(C#N)c2ccccc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
1-Cyano-4-fluoronaphthalene (100 mg, 0.58 mmol), 2-methylpiperidine (0.28 mL, 2.3 mmol) and DBU (0.01 mL, 59 μmol) were dissolved in pyridine (2 mL) and stirred at 60° C. for 3 days. The temperature was raised to 110° C. and the stirring was continued for 10 days. The reaction was worked up in the same way as for 198RL60. The crude compound was purified by preparative TLC followed by preparative HPLC to give the title compound (27.4 mg, 19%) as a colourless oil, which was stored under argon atmosphere.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](=[O:28])[NH:11][C@@H:10]3[CH2:9][CH2:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=4[N:5]4[CH:1]=[CH:2][N:3]=[C:4]34)[CH2:25][CH2:26]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: -20 °C
Yield: 93.58 %

Procedure:
Concentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness prior to use in the coupling reaction. Dissolve 15.0 g (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine and 18.03 g 1-[(4-Chlorobenzoyl)amino]cyclopropanecarboxylic acid in 120 ml of dichloromethane and 32 ml triethylamine. After cooling to −20° C., add 53.0 ml (1.2 eq.) of T3P within 40 minutes maintaining a temperature of −19° C. Allow the reaction to warm to room temperature over night. Test by HPLC for complete consumption of starting materials. After aqueous quench (75 ml of water) at 0 to 6° C. and further dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases. Wash the organic layer two times with 75 ml of water and then back-extract the combined aqueous layers once with 75 ml of dichloromethane. Concentrate the organic extract phases (420 ml) removing 290 ml of solvents (beginning precipitation of solids). Add 240 ml of isopropyl acetate and then remove a further 250 ml of solvents. Warm the resulting thick suspension to 70° C., add 30 ml of n-heptane and slowly cool the suspension to room temperature over night. Filter the suspension via glass filter nutsch and wash the filter cake with n-heptane. After drying with a rotavap, results in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral). LC-MS (mass spectrometry) (m/z): 421.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:25](=[O:32])[CH:26]=[C:27]([CH2:30][OH:31])[O:28][CH:29]=1)[CH2:13][CH3:14]>ClCCl.C(OCC)C>[O:32]=[C:25]1[C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:33]=[CH:34][CH:35]=[CH:36][C:15]=2[CH2:12][CH2:13][CH3:14])=[CH:29][O:28][C:27]([CH:30]=[O:31])=[CH:26]1
Reactant: CCCc1ccccc1OCCCCCOc1coc(CO)cc1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1ccccc1OCCCCCOc1coc(C=O)cc1=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a stirred solution of 4.44 g (20.6 mmole) of pyridinium chlorochromate in 50 ml of dichloromethane was added 3.46 g (10 mmole) of the title alcohol of Example 4 dissolved in 50 ml of dichloromethane. The resulting slurry was stirred at room temperature for twenty-four hours, then diluted with 100 ml of diethyl ether. The insolubles were removed by decanting and the supernatant was concentrated in vacuo. Purification by column chromatography afforded 1.4 g of the title compound, m.p. 95°-96°.
Reaction SMILES: [OH-:1].[K+].O.[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12](N)=[O:13]>C(O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([OH:1])=[O:13]
Reactant: [OH-]
Reactant: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(N)=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)O
Yield: 59.8 %

Procedure:
In an egg-plant type flask were charged 7.66 g of 85% potassium hydroxide, 3 ml of water, 60 ml of ethanol, and 3.0 g of the compound obtained in Step 6, and the mixture was refluxed for 10 hours. Ethanol was removed by distillation under reduced pressure, and 30 ml of water was added to the residue. The mixture was adjusted to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by distillation under reduced pressure to obtain 2.6 g of a crude product. Purification by silica gel column chromatography gave 1.8 g (59.77%) of the titled compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12](=[O:15])[CH2:13][OH:14])[CH2:8][CH2:9][CH3:10].Cl.C(=O)(O)[O-].[Na+]>>[CH2:7]([O:11][C:12](=[O:15])[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOC(=O)CO
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
84 g of 3,4-dihydro-2H-pyran and 132 g of glycolic acid butyl ester are dissolved at room temperature. To this solution are added 0.5 ml of concentrated hydrochloric acid, whereupon the temperature immediately rises to 90°. The solution is cooled to room temperature and stirred for 2 hours. After the addition of 1 g of sodium bicarbonate, the crude product is distilled under 17 Torr to obtain 2-(tetrahydropyran-2-yloxy)-acetic acid butyl ester, B.P. 127°/17 Torr.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: OCC#CCO
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)ncnc1OCC#CCO
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of DMPU was added 2.8 g sodium hydride in portions. After completion of the addition stirring was continued for 1.5 h followed by the addition of 2.78 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide. The mixture was heated to 90° C. and stirred for 65 h. The solvent was removed in vacuo, the residue was taken up in 250 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. Column chromatography of the crude product on silica gel eluting with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. Beige crystals were obtained for analytical purposes after crystallisation of a part of the isolated product from 2-propanol. LC-MS: tR=4.50 min, [M+1]+=485.27, [M−1]−=483.41.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:15](Br)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[CH:11]=[O:12])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 40 %

Procedure:
To 6-chloro-1H-indole-2-carbaldehyde (1 equiv.) in DMF at 0° C. was added NaH (1.25 equiv.) portionwise followed by benzhydryl bromide (1.46 equiv.) and Bu4Nl (0.05 equiv.). The mixture was stirred at rt for 42 h before quenching with cold 0.4N HCl at 0° C. After neutralization, the aqueous layer was extracted with ether and the organic layer was washed with cold H2O and dried. Flash chromatography on silica gel gave 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde in 40% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[O:26]=[C:21]1[NH:22][C:23](=[O:25])[C:24](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=3)=[CH:5][CH:4]=2)[S:20]1
Reactant: CCOC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CCOC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 80 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 11.7 g (46 mmol) of ethyl 4′-formylbiphenyl-3-carboxylate with 5.4 g (46 mmol) of 2,4-thiazolidine dione, 13 g (83%) of the expected product are obtained.