Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:19]#[N:20])[C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:19]#[N:20])[C:13]=3[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: N#Cc1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1nccc2c1ncn2-c1ccc(N)cc1
Yield: 30.7 %

Procedure:
In 100 mL of methanol, 240 mg (0.9 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved, and 170 mg of 10% palladium carbon was added thereto and the mixture solution was refluxed with stirring in a hydrogen atmosphere for one hour. The palladium carbon was removed by Celite filtration and the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by a silica gel column (dichloromethane:methanol=40:1) to obtain 65 mg (30%) of a target product as a pale yellow solid.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:16][C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6].C(OC(=O)C)(=[O:21])C>>[S:5]([C:8]1[S:16][C:15]2[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: CN(C)C=NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Reactant: CC(=O)OC(C)=O
Product: NS(=O)(=O)c1cc2[nH]c(=O)ccc2s1
Temperature: 140 °C
Yield: 33 %

Procedure:
A suspension of N,N-dimethyl-N'-(4-oxido-thieno[3,2-b]pyridine-2-sulfonyl)formamidine (6.23 g, 22.6 mmol) in acetic anhydride (70 ml), under a nitrogen atmosphere, was heated at 140° C. for 20-22 hours to give a dark solution. The excess acetic anhydride was removed on a rotary evaporator and 6 N HCl (90 ml) was added to the residue and it was warmed at 80° C. for four hours. This reaction mixture was cooled and ice was added as product began to precipitate. Upon standing several crops were collected by filtration. The combined crude product (2.2 g) was dissolved in a large volume of boiling water, filtered and allowed to cool. Pure product was obtained (1.72 g, 33% yield). This material was recrystallized by dissolution in a minimum volume of hot dimethylsulfoxide. This solution was treated with charcoal, filtered, and diluted with ethanol as product crystallized (1.3 g), m.p. >300° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]([F:8])([CH3:7])[CH3:6])[CH2:3][OH:4].C1C[O:12][CH2:11]C1>C(Cl)Cl>[F:8][C:5]([CH:2]1[CH2:3][O:4][C:11](=[O:12])[NH:1]1)([CH3:7])[CH3:6]
Reactant: CC(C)(F)C(N)CO
Reactant: C1CCOC1
Solvent: ClCCl
Product: CC(C)(F)C1COC(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-carbonyldiimidazole (530 mg, 3.27 mmol in THF (5 mL) was added slowly a solution of 2-amino-3-fluoro-3-methylbutan-1-ol (360 mg, 2.97 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 hr, was diluted with DCM and stirred for additional 30 min. The separated organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] to provide 4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 148.0 (M+H)+; Rt-0.32 min. 1H NMR (400 Mhz, CDCl3) δ ppm 6.30 (br. s., 1H), 4.39-4.54 (m, 1H), 4.26 (dd, J=8.9, 5.1 Hz, 1H), 3.84-3.99 (m, 1H), 1.29-1.45 (m, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=O)[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:35][NH2:36]>CO>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([NH:36][CH3:35])=[O:32])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
70 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate prepared in Example 3 was dissolved in 5 mL of 2M methylamine in methanol in a sealed tube. The mixture was stirred at 50° C. for 24 hours. The solvent was then removed and the residue purified using TLC with a 15:1 dichloromethane:methanol solution to yield (1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13](/[CH:28]=[CH:29]/[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: BrC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2/C=C/Cc1ccccc1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[C:9]([CH3:12])[NH:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:7](=[O:13])[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH:10]=[C:9]1[CH3:12]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccc(F)cc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccc(F)cc2C(=O)N1CCCCBr
Reaction time: 0.5 h

Procedure:
416 mg of 4,5-dihydro-7-fluoro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 15 ml of dimethylformamide, then 113 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 1 ml (3.6 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:27]([CH3:40])=[C:28]([CH3:39])[C:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[C:30]=4[C:37]=3[CH3:38])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CCCCCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:31]2([OH:36])[C:30]3[C:37]([CH3:38])=[C:26]([N:23]4[CH2:24][CH2:25][N:20]([C:17]5[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=5)[CH2:21][CH2:22]4)[C:27]([CH3:40])=[C:28]([CH3:39])[C:29]=3[O:33][C:32]2([CH3:34])[CH3:35])=[CH:3][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 91 %

Procedure:
Using 1-bromo-4-(trifluoromethyl)benzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 91%. mp. 181–183° C. (hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CCCC(C)CBr
Reactant: COc1ccc(O)cc1
Solvent: CO
Product: CCCC(C)COc1ccc(OC)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
Sodium metal (6.99 g, 304 mmol) was dissolved in dry methanol (120 ml) under Ar to give a 2.5M solution of sodium methoxide. A solution of 4-methoxyphenol (31.4 g, 253 mmol) in dry methanol (150 ml) was added and this mixture was heated to reflux for 30 min. After cooling to room temperature, a solution of 1-bromo-2-methylpentane (46.0 g, 279 mmol) in dry methanol (100 ml) was added. The mixture was then heated to reflux for 16 hours. The solvent was removed in vacuo, the residue dissolved in ether (200 ml), washed with dilute aqueous sodium hydroxide (250 ml) and water (500 ml), dried over MgSO4 and concentrated in vacuo again. Distillation at 80° C./0.5 mm Hg afforded 14.0 g (27%) 1-methoxy-4-(2'-methylpentyloxy)benzene, 1H NMR (250.1 MHz, CDCl3): δ=0.94(t,3 H), 1.02 (d, 3 H), 1.16-1.56 (m, 4 H), 1.93 (m, 1 H), 3.64-3.82 (m, 2 H), 3.77 (s, 3 H), 6.81-6.89 (m, 4 H), 13C NMR (100.6 MHz, CDCl3): δ=14.3, 17.0 (both CH3), 20.1, 35.8 (both CH2), 33.0 (CH), 55.7 (OCH3), 73.9 (OCH2), 114.6, 115.4 (arom. CH), 153.5, 153.6 (ipso C). IR(film): 2956(m), 1509(s), 1232(s), 1045(m), 824(m) cm-1, MS(EI) :m/z (%)=208 (100), 124 (32), Calcd. for C13H20O2 : C 74.96, H 9.68 found: C 75.03, H 9.70.
Reaction SMILES: [CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][C@@H:46]([C:48]2[CH:59]=[CH:58][C:51]3[O:52][C:53]([CH3:57])([CH3:56])[O:54][CH2:55][C:50]=3[CH:49]=2)[O:45][C:44]1=[O:60])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C@@H:46]([C:48]4[CH:59]=[CH:58][C:51]5[O:52][C:53]([CH3:56])([CH3:57])[O:54][CH2:55][C:50]=5[CH:49]=4)[O:45][C:44]3=[O:60])[CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)C5CCCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-({2-(trimethylsilyl)ethoxy}-methyl)benzenesulfonamide (508 mg) in DMF (8 ml) under nitrogen at 200 was treated with sodium hydride (60% dispersion in mineral oil, 58 mg) and the mixture was stirred 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (400 mg) in DMF (2 ml) was added and the mixture was stirred at 20° for 72 h. Phosphate buffer solution (pH 6.5, 10 ml) and water (20 ml) were added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×30 ml), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE (1:1) gave the title compound (530 mg). LCMS RT=4.47 min, ES+ve 793 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[O:15]C.[Cl-].[NH4+]>ClC1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:15]
Reactant: CNC(=O)CCC(=O)c1c(OC)cccc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Clc1ccccc1
Product: CNC(=O)CCC(=O)c1c(O)cccc1OC

Procedure:
N-Methyl 3-(2,6-dimethoxybenzoyl)propionamide was demethylated with ammonium chloride in chlorobenzene to give N-methyl 3-(2-hydroxy-6-methoxybenzoyl)propionamide, m.p. 125° which may also be prepared from a by-product, N-methyl 3-(2,6-dihydroxybenzoyl)propionamide, by selective methylation with methyl iodide and potassium carbonate in acetone.
Reaction SMILES: O(C)[Na].[Br-].[O:5]1CCCO[CH:6]1[CH2:11][P+](CCCC)(CCCC)CCCC.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30]([CH:31]=O)=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1.O>CN(C=O)C>[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30](/[CH:31]=[CH:11]/[CH:6]=[O:5])=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCCO1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Agent: CO[Na]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/C=O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
At room temperature, NaOCH3 (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C. Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1 M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50° for overnight, the mixture was poured over water, and extracted with ether, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2 N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-1. MS (EI): 237 (M).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N3CCCC3)nc2)CC1

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.71 g, 2.0 mmol), pyrrolidine (2.0 g, 20 mmol), potassium tert-butoxide (0.45 g, 4.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and 1.2-dimethoxyethane was stirred at reflux overnight. Water (40 ml) was added and the mixture was extracted twice with ethyl acetate (20 ml) Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as free base. Yield 0.21 g, 30%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cc(F)cc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.19 g, 1.07 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 0.19 g, 44%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N#N.N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1COCC1.O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:3][CH2:2][CH2:1][OH:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 25 °C
Yield: 20 %

Procedure:
To a stirred solution of ethylene glycol (2.44 mL; 6.0 eq.) in dry THF (35 mL), under inert atmosphere (N2), were added imidazole (497 mg; 1.0 eq.) and a solution of tert-butyldimethylsilyl chloride (1.10 g; 1.0 eq.) in dry THF (35 mL). The reaction mixture was stirred at rt over the weekend. Water was added and THF was removed under vacuum. The residual aq. layer was extracted with EA (3×) and the combined org. layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained, after purification by CC (Hept/EA 100:0 to 60:40), as a colorless liquid (258 mg; 20% yield).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 119.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine-3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH:12][C:22](=[O:23])[CH2:21][C:20]([F:26])([F:25])[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1ccc(N)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NC(=O)CC(F)(F)F)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 2-((tert-butyldimethylsilyloxy)methyl)-4-methoxyaniline (14.0 g), 3,3,3-trifluoro-propionic acid (7.30 g, 57.0 mmol), EDCI (15.0 g, 76.5 mmol), HOBT (11.0 g, 80.2 mmol) and NMM (22 mL, 157 mmol) in anhydrous CH2Cl2 (200 mL) was stirred at 20° C. for 2 hours. The mixture was diluted with CH2Cl2 (100 mL), the organic layer was washed with 1M HCl (100 mL), H2O (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[CH:12](OCC)=[O:13].[K].CC(C)([O-])C>C1(C)C=CC=CC=1>[OH:13][CH:12]=[C:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10]#[N:11]
Reactant: Cc1cccc(C)c1CC#N
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1C(C#N)=CO
Reaction time: 2 h

Procedure:
126 g (0.87 mol) of 2,6-dimethylphenylacetonitrile are dissolved in 450 ml toluene and combined with 450 ml of ethyl formate. The mixture is cooled to a temperature of −10° C. and 144 g (1.29 mol) of potassium-tert.-butoxide are added in batches, so that the temperature does not exceed −5° C. It is left to react for a period of 30 minutes (min) at −5° C. and then for 2 hours (h) at ambient temperature. It is then extracted twice with 500 ml of water, the aqueous phase is made acidic with 100 ml of concentrated hydrochloric acid and extracted twice more with 500 ml of methylene chloride (dichloromethane). The organic phase is dried and concentrated by evaporation in vacuo. The residue is recrystallised from petroleum ether. Yield: 139 g (92% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=34)=[CH:4][CH:3]=2)=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(-c4cc5ccccc5s4)cc3)c12
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine (30.0 mg, 0.0874 mmol), 1-benzothiophen-2-ylboronic acid (18.7 mg, 0.105 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) in 1,4-dioxane (2 mL, 30 mmol) and H2O (0.2 mL, 9 mmol) was degassed and refilled with nitrogen (3×). The reaction was microwaved on 300 watts, PowerMAX enabled, 100° C. for 30 min. For the workup, the reaction was concentrated in vacuo to a solid and purified by 10 g Jones Chromatography column wetted with DCM, dried loaded the product, eluted with DCM to 5% MeOH in DCM], which afford 8.4 mg (24%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3); 6=2.03-2.14 (m, 1H), 2.16-2.27 (m, 1H), 2.48-2.59 (m, 2H), 2.61-2.74 (m, 2H); 3.78-3.89 (m, 1H), 6.93 (d, J=5.56 Hz, 1H), 7.14 (d, J=5.56 Hz, 1H), 7.33-7.43 (m, 2H), 7.66 (s, 1H), 7.74 (d, J=8.59 Hz, 2H), 7.80-7.92 (m, 4H). HPLC: tR=2.71 min. (Open Lynx polar—5 min.). MS (ES+): m/z 379.80/380.91 (100/60) [MH+].