Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:25][CH2:24][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1>CCOCC.CCCCCCC>[F:22][C:19]([F:20])([F:21])[CH:18]([CH3:23])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:4][CH2:3][C:2](=[O:1])[CH2:25][CH2:24]3)[C:9]2=[O:10])=[CH:12][CH:13]=1
Reactant: CC(Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCCC
Product: CC(Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F

Procedure:
This material was obtained in analogy to example 108, step 4 by Swern oxidation of 8-hydroxy-2-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one (230 mg, obtained in example 162, step 3) as a colorless solid (230 mg). Rf: 0.3 (silica gel, ether/heptane 1:1).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])O.[Na+].O>C(OCC)C>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH:7]=[CH:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:41][CH:40]=2)=[N:47][CH:46]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1C1OCCO1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(C=CC3OCCO3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.44 g of (1,3-dioxolan-2-yl)-methyl-triphenylphosphonium bromide in 70 ml of diethyl ether is treated with 1.68 g of potassium t-butylate within 5 minutes while gassing with nitrogen. The orange suspension is stirred for 30 minutes, then cooled to 0° C. and treated within 10 minutes with a solution of 3.11 g of 6-[4-(octyloxy)phenyl]-3-pyridinecarboxaldehyde (prepared in accordance with Example 2) in 25 ml of diethyl ether. The reaction mixture is stirred at room temperature for a further 3 hours and then treated with 0.6 g of sodium hydrogen carbonate and with 20 ml of water. The organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is taken up in hexane and 20 ml of 80 percent aqueous methanol. The phases are separated and the hexane phase is washed with 10 ml of 80 percent methanol, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) gives 5-[2-(1,3-dioxolan-2-yl)vinyl]-2-[4-(octyloxy)phenyl]-pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][N:27](S(C4C=CC(C)=CC=4)(=O)=O)[C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:1]([O:5][C:6](=[O:53])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:48](=[O:52])[N:49]([CH3:50])[CH3:51])=[O:13])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
[2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester (84 mg, 0.113 mmol) was dissolved in a solution of tetrahydrofuran (20 ml) and methanol (5 ml). A solution of aqueous potassium hydroxide (50% w/v, 5 ml) was added to the reaction mixture, and the combined mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% [10% methanol in ethyl acetate] in hexanes) to give 61 mg (92%) of [2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: m/z 587.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)CCC2CCC(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 55 °C

Procedure:
A solution of 13 g of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester in 250 ml of tetrahydrofuran is treated with 14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride. The mixture is heated to 55° C. and a solution of 5.5 g of triethylamine in 400 ml of tetrahydrofuran is added dropwise over a two hour period. The mixture is stirred and heated at 55° C. for 16 hours. The warm mixture is filtered through filter aid to remove triethylamine hydrochloride and concentrated at reduced pressure. Chromatography over silica using a Waters Prep 500 HPLC apparatus yields 1-(3-benzyloxy-4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid benzyl ester with mp 92°-95° C. after concentration and crystallization.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][CH:8]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl ((1S,2S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)carbamate (3.49 g, 10.08 mmol) in dry DCM (67 ml) at 0° C. was added 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; 2.15 g, 12.09 mmol). The reaction was allowed to warm to room temperature overnight. A further portion of portion of 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; 1.70 g, 9.56 mmol) was added and the reaction stirred for an additional 24 hours. The reaction was concentrated in vacuo and then purified by column chromatography (silica, 0-30% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C1COCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 52.3 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (157 mg, 0.5 mmol) in dry THF (3 mL) stirred under N2 at 25° C. was added dropwise propionyl chloride (0.05 mL, 0.58 mmol). A yellow solid formed at once. After 45 minutes the solid was collected by filtration and washed with ether and dried. Recrystallized from wet methanol afforded the desired product (97 mg, 47%), mp 265-266° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])=[CH:14][CH:15]=1)#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: COCCOCc1ccc(C=O)cc1
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(COCCOC)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Dimethyl[(2-diazo-3-oxo)propyl] phosphonate was added in 4 portions to a suspension of potassium carbonate (4.96 g, 36 mmol), the product of Step B (3.78 g, 18 mmol), and methanol (50 mL). The reaction was stirred for 16 hours. and concentrated in vacuo. The residue was taken up in ether, washed with water (3×), dried (potassium carbonate), and concentrated. The crude product was purified by silica gel chromatography (hexane:ethyl acetate) to provide the title compound (2.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH:52]1[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH:52]1[NH:51][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:20]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: NC1Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4Cc5ccccc5C4)cc3)c(C#N)cc21
Reaction time: 3 h
Yield: 75.3 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (from Example 7, Step B) (12 mg, 0.034 mmol), HBTU (15 mg, 0.041 mmol) were diluted with N-methylpyrrolidone (1 mL) followed by the addition of 2-aminoindan (4.5 mg, 0.034 mmol), N,N-diisopropylethylamine (0.015 mL, 0.085 mmol) and DMAP (1.2 mg, 0.010 mmol). After stirring for 3 hours, the reaction was loaded directly onto a Biotage 12i cartridge eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (12 mg, 75% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[C-:25]#[N:26].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:25]([CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1)#[N:26]
Reactant: [C-]#N
Reactant: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 27.7 %

Procedure:
To a suspension of 2.0 g (6 mmol) of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 20 ml of acetonitrile was added 3.9 g (60 mmol) of potassium cyanide and 0.1 g of 18-crown-6; the mixture was heated to reflux for 2.5 hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel using ethyl acetate/methanol (8:2) as eluent; yielding 0.55 g of the title compound, melting point 175°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[OH:11])=[C:4]([CH3:24])[CH:3]=1.CN(C)C=O.[CH2:30](Br)[CH3:31].[H-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[O:11][CH2:30][CH3:31])=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OCc1ccccc1C(O)c1nccn1C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(c1ccccc1COc1ccc(Cl)cc1C)c1nccn1C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a mixture of 0.34 g (0.9 mmol) of 2-[2-(4-chloro-2-methylphenoxymethyl)-α-hydroxybenzyl]-1-methylimidazole, 3 ml of N,N-dimethylformamide and 0.13 ml (1.8 mmol) of ethyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-ethoxybenzyl]-1-methylimidazole (0.30 g, 89.9%) as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[O:27][C:28]1[O:32][C:31]([C:33](Cl)=[O:34])=[CH:30][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[O:27][C:28]1[O:32][C:31]([C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:34])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:40])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:40])=[O:35])[O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (1.53 g, 3.17 mmol) in THF (28 mL) was added NaIO4 (1.36 g, 6.34 mmol) followed by the addition of water (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then filtered through celite, and concentrated in vacuo. The residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo. To the intermediate aldehyde (˜1.4 g) was added 2-methylpropan-2-ol (17 mL) and 2-methylbut-2-ene (9 mL, 85.08 mmol) and the reaction mixture was cooled to 0° C. A solution of NaClO2 (938 mg, 8.29 mmol) and NaH2PO4 (1.15 g, 8.31 mmol) in water (17 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, then extracted with ethyl acetate (4×50 mL) and the combined organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo to give 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid as a white foam (1.48 g, 100%). ESI-MS m/z calc. 466.6. Found 467.5 (M+1)+; Retention time: 1.27 minutes (3 min run).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH2:10][C:3]1=2
Reactant: NC1CCCc2sccc21
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2sccc21

Procedure:
Alternatively, 5.7 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride is stirred in 20 ml. of toluene at 97° C., and phosgene is slowly introduced into the mixture via a capillary delivery tube. The mixture is heated to reflux temperature, and the flow of phosgene is continued until most of the amine hydrochloride disappears. The mixture is then filtered to remove unreacted amine hydrochloride, and the filtrate is evaporated to dryness under reduced pressure to give the 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[N:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[N:3]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1OC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(N=[N+]=[N-])nc1OC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a suspension of 22.0 g of 2-bromo-5,6-dimethoxy-3-nitropyridine (example E4) in 50 ml DMSO were added 16.0 g sodium azide. The reaction mixture was stirred for 24 h at 50° C. Additional 3.20 g sodium azide were added and after stirring for additional 44 h the reaction was completed. The solvent was removed under vacuum and the resulting residue was extracted with dichloromethane (3×100 ml). The solvent was removed and the residue was purified by flash chromatography (petroleum ether/ethyl acetate) to yield the title compound.
Reaction SMILES: CN(C)C1C=CC(CN[C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=CC=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18]
Reactant: NCCc1ccccc1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Product: O=C(CCCNC(=O)NCCc1ccccc1)NO

Procedure:
Compound 1 was prepared using the methodology described for the preparation of compound 2, by substituting 4-dimethylaminobenzylamine dihydrochloride with phenethylamine. 1H NMR (CD3OD) δ 7.30-7.15 (m, 5H), 3.34 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.09 (t, J=7.5Hz, 2H), 1.73 (m, 2H). 13C NMR (CD3OD) δ 172.7, 161.3, 140.9, 130.0, 129.6, 127.4, 42.8, 40.4, 37.7, 31.3, 27.8.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[CH3:23][C:24]([CH3:39])([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[C:24]([CH3:23])([CH3:39])[C:28]([NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])=[O:29])[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]1=2)[CH3:14]
Reactant: CCOCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CCOCCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-ethoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (80%). White solid. MS: m/e=542(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N1C=CC=CC=1>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a stirred solution of methyl 4-amino-2-fluorobenzoate (800 mg, 4.6 mmol, 1.0 eq) in acetone (10 mL) was added phenyl chloroformate (0.6 mL, 4.6 mmol, 1.0 eq) and followed by pyridine (1.1 mL, 13.8 mmol, 3.0 eq) at 0° C. and stirred at RT for 1 h. The acetone in the RM was evaporated and diluted with water (50 mL) extracted with EtOAC (2×100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was washed with n-pentane to yield methyl 2-fluoro-4-(phenoxycarbonylamino)benzoate (1.2 g, 89.6%) as white solid (TLC: EtOAc/PE (2:3); Rf: 0.3).
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[N:11]=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5]1)[C:2]#[CH:3].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[N:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]1[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[C:2]#[CH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC[C@H]1Nc2cccnc2NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: C#CC[C@@H]1C(=O)Nc2ncccc2N1S(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of (R)-2-(prop-2-ynyl)-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (150 mg, 0.8 mmol) (300 mg of crude from last step) and 4-methylbenzene-1-sulfonyl chloride (229 mg, 1.20 mmol) in pyridine (3 mL) was stirred at room temperature for 3 h. The reaction mixture was treated with 10 % HCl (5 mL) and extracted with ethyl acetate, dried over Na2SO4 and evaporated. Flash chromatography (SiO2, DCM to DCM/ethyl acetate=4:1 to 3:1 to 2:1 to 1:1) gave the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (137 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (115 mg, 0.5 mmol) according to the general procedure M. Obtained as a light red solid (139 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(CO)=C(c2ccc(Cl)cc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 494F in dichloromethane (120 mL) at 0° C. was added Dess-Martin periodinane (17.7 g) and the reaction was allowed to warm to room temperature. The reaction was diluted with dichloromethane (200 mL), washed twice with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The crude product was filtered through a silica gel plug to give the title compound.