Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(O)C>[CH2:38]([O:37][C:35]([CH2:34][NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 96 h
Yield: 49.3 %

Procedure:
In 10 ml of ethanol is dissolved 0.5 g of benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride obtained in Example 5, and triethylamine (0.49 g) and ethyl bromoacetate (0.46 g) are added to the solution. After the solution is stirred for 4 days, the solution is dried under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:3) to give 0.28 g of benzyl 3(S)-ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH:22]=[O:23])[CH:21]=1)[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(CO)c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C=O)c2)CC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[3-bromo-5-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (0.47 g, 1.2 mmol) in DCM (20 mL) at 0° C. was added Dess-Martin periodinane (0.67 g, 1.6 mmol). After stirring for 2 hours, the reaction solution was poured into saturated NaHCO3, and extracted with DCM (3×). The combined extracts were washed with brine. The organic layer was dried over sodium sulfate, decanted and evaporated to give the desired product that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(c2ccc(Br)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 8-(4-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.02 g) and half concentrated hydrochloric acid is heated for 12 hours at 50° C., poured on ice and aqueous NaOH solution (4 M) is added until pH ˜7-8. Then the mixture is extracted with ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo to give the title compound. LC (method 2): tR=0.96 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.I[CH3:21].O>CN(C)C=O>[F:10][C:8]1[CH:7]=[C:6]([N:11]([CH3:21])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccn1)c1cc(F)cc(F)c1
Temperature: 65 °C
Yield: 56 %

Procedure:
To a suspension of 80% sodium hydride (1.22 g, 41 mmol) in anhydrous dimethylformamide (90 mL), was added dropwise a solution of N-(3,5-difluorophenyl)-2-pyridinecarboxamide, prepared by the process of Example 1, Step 1 (8.71 g, 37 mmol) in dimethylformamide (30 mL). The reaction mixture was warmed to 65° C. for 1 hour and then treated with iodomethane (2.60 mL, 42 mmol) at room temperature. After 2.5 hours the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with 75% brine, dried, preabsorbed onto silica gel, and flash chromatographed (300 g, elution with 40% ethyl acetate in petroleum ether) to yield pure N-(3,5-difluorophenyl)-N-methyl-2-pyridinecarboxamide (5.16 g, 21 mmol, 56%, m.p. 102°-104° C.), which was reacted with Lawesson's reagent (4.36 g, 11 mmol) in anhydrous toluene (65 mL) at reflux temperature for 1.5 hours. The toluene was evaporated and the residue was dissolved in dichloromethane, preadsorbed onto silica gel, flash chromatographed (300 g, elution with 10% ethyl acetate in petroleum ether), and recrystallized from ethyl acetate in petroleum ether to afford a yellow solid (2.36 g, 24%), m.p. 131°-134° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]1[CH:43]([NH2:45])[CH3:44])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:31]1[CH:43]([NH:45][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH3:44])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)c1nccc(-n2ccc3ccccc32)n1
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Product: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[indol-1-yl]pyrimidine (125 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine (EXAMPLE 28; 166 mg) according to the procedure described in EXAMPLE 14, Step E. Mass spectrum (ESI) 557.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41]O)[CH2:36]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:41][CH:37]4[CH2:38][CH2:39][CH2:40][N:35]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:36]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCCCCCN1CCCC(CO)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCN1CCCC(COc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)C1
Yield: 82.2 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-hexyl-3-piperidine methanol (1.69 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 1 to give 1.41 g of the title compound. Yield: 82%. MS(FD) 572(M+). EA calculated for C35H41NO4S: C, 73.52; H, 7.23; N, 2.45. Found: C, 73.25; H, 7.08; N, 2.71.
Reaction SMILES: [NH:1]1[C:5]2([CH2:14][CH2:13][C:8]3(OCC[O:9]3)[CH2:7][CH2:6]2)[C:4](=[O:15])[NH:3][C:2]1=[O:16].Cl>CCO>[NH:1]1[C:5]2([CH2:6][CH2:7][C:8](=[O:9])[CH2:13][CH2:14]2)[C:4](=[O:15])[NH:3][C:2]1=[O:16]
Reactant: O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1
Agent: Cl
Solvent: CCO
Product: O=C1CCC2(CC1)NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 9,12-dioxa-1,3-diazadispiro[4.2.4.2]tetradecane-2,4-dione (6.33 g, 28.0 mmol) in HCl (6N) (28 mL, 168 mmol) and EtOH (66.0 mL) was stirred at RT for 18 hours. The mixture was partially evaporated (about ½ volume), cooled in an ice bath and brought to a pH of approximately 10. The aqueous layer was extracted with DCM (2×200 mL), and the aqueous layer concentrated. The residue was triturated with THF (2×100 mL), and solids were removed by filtration. The filtrate was evaporated to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[CH3:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cc1cccc(C)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2,6-dimethylbenzaldehyde (0.9 g) in acetic acid (2 mL) and MeOH (5 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 18 hr and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (elution with a gradient of 15-25% EtOAc in CH2Cl2) providing the title compound (142 mg, 75%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6 (d, 2H), 7.5 (m, 1H), 7.35 (s, 1H); 7.2 (m, 1H), 7.1 (overlapping m, 2H), 6.8 (d, 2H), 4.3 (s, 2H), 2.4 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH:21]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(C)C(S([NH:48][N:49]=[C:50]([CH3:54])[CH:51](Cl)Cl)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:18][CH:17]=[C:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([N:5]3[CH2:4][C@H:3]([CH2:2][N:1]4[CH:51]=[C:50]([CH3:54])[N:49]=[N:48]4)[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:29])[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Reactant: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Yield: 46.7 %

Procedure:
(5S)-5-(Aminomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-diflurophenyl]-1,3-oxazolidin-2-one (Intermediate 54) (3.20 g, 8.01 mmol) was reacted with diisopropylethylamine (5.60 ml, 32.04 mmol) and 1,1-dichloroacetone toluenesulfonylhydrazone (2.8 g, 9.6 mmol) as described for Example 3. Chromatography on silica gel with ethyl acetate gave 1.74 g of the title product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OCCCBr)cc2N1
Yield: 88 %

Procedure:
7-hydroxy-3,4-dihydroquinolin-2(1H)-one (195 mg, 1.2 mmol), 1,3-dibromopropane (960 mg, 4.8 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 3) (300 mg, 88%) as a white solid. HPLC: 99%, RT 2.775 min. MS (ESI) m/z 284.0 [M+H]+.
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[CH2:11][N:12]1[CH2:19][C@H:18]2[NH:20][CH2:21][C@@H:13]1[CH2:14][CH:15]=[CH:16][CH2:17]2.C(OCC)(=O)C.[O:28]1[CH2:30][CH:29]1[CH2:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[CH:36][NH:37]2>C(O)C>[NH:37]1[C:38]2[C:34](=[C:33]([O:32][CH2:31][CH:29]([OH:28])[CH2:30][N:20]3[CH2:21][CH:13]4[N:12]([CH2:11][C:2]5[CH:3]=[CH:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=5)[CH2:19][CH:18]3[CH2:17][CH:16]=[CH:15][CH2:14]4)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2Cc1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2Cc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(COc1cccc2[nH]ccc12)CN1CC2CC=CCC1CN2Cc1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-ylmethyl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (30 mg, 0.064 mmol), ethyl acetate (0.5 mL) and 4-oxiranylmethoxy-1H-indole (50 mg, 0.26 mmol) were placed in a μW tube with ethanol (3 ml) and heated to 95° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via flash chromatography (15% Ethyl acetate/heptane to 100% Ethyl acetate) to yield the title compound as a residue.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.I(C1C=CC=CC=1C(O)=O)(=O)=O.[OH-].[Na+]>CS(C)=O>[CH:2]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(CO)nc3c(N4CCOCC4)ccnn23)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C=O)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 41b (3.2 g, 7.7 mmol) in DMSO (22 mL) was added 2-iodoxybenzoic acid (3.4 g, 12 mmol) in portions. The reaction mixture was stirred overnight at rt and treated with 1N NaOH (50 mL). The solids formed were collected by filtration and washed with Et2O (2×50 mL) to obtain compound 41c as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H29N5O4: 416.2 (M+H). found: 416.2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[BH4-].[Na+].O>CO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1
Reactant: O=Cc1cnc(C2OCCO2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cnc(C2OCCO2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbaldehyde (7.00 g) in methanol (30 mL) was slowly added sodium borohydride (0.53 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.59 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 188 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[C:14]([NH2:28])=[N:15][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:17]=1>>[NH2:28][C:14]1[C:13]([CH3:12])=[N:17][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:9](=[O:11])[C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:15]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ncc(Cl)cc4Cl)cc32)N=C1N
Yield: 63.5 %

Procedure:
The title compound (59 mg, 62% yield) was prepared as described for Example 13a starting from 3,5-dichloropicolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-2.01 (m, 2 H), 2.22 (s, 3 H), 4.29-4.49 (m, 2 H), 6.57 (s, 2 H), 6.75-6.85 (m, 2 H), 7.48-7.57 (m, 1 H), 8.41 (d, 1 H), 8.68 (d, 1 H), 10.39 (s, 1 H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32]C(=O)OC(C)(C)C)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[C:22]([NH:21][C@@H:20]([CH3:41])[C:19]([NH:18][C@@H:17]([CH3:43])[C:16]([NH:15][C@@H:14]([CH3:45])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:46])=[O:44])=[O:42])=[O:40]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 3, except using material from Example 75 (100.2 mg, 0.129 mmol), CH2Cl2 (2 mL), TFA (2 mL, 26 mmol) and stirring at room temp for 2 h, the title compound (quantitative yield) is isolated as an off white solid, as a TFA salt, that is used directly “as is” in the next coupling step. LC/MS (Condition A): ret. T=1.88 min, (M+H)+ 562.37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:42]=[C:43]=[O:44])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[C:31]([NH:42][C:43](=[O:44])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 42 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with decanoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 92 (152 mg, 42%) as crystals. Mp. 84-86° C. Rf 0.37 (EtOAc).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:18]([Br:22])=[CH:17][C:14]=1[C:15]#[N:16])=[N+]=[N-]>C1(C)C=CC=CC=1>[Br:22][C:18]1[CH:19]=[C:20]([Cl:21])[C:13]([N:12]2[CH:11]=[C:5]3[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]3=[N:1]2)=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(Br)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: N#Cc1cc(Br)cc(Cl)c1-n1cc2cncc(F)c2n1
Yield: 58 %

Procedure:
A solution of 2-{[1-(4-azido-5-fluoropyridin-3-yl)meth-(E)-ylidene]amino}-5-bromo-3-chlorobenzonitrile (˜22.6 mmol) in toluene (100 mL) was heated under reflux for 5 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was collected by filtration and dried to afford the title compound as an off-white solid (4.61 g, 58% yield over two steps). 1H NMR (400 MHz, DMSO-d6): δ 9.37 (d, J=2.7 Hz, 1H), 9.27 (d, J=2.6 Hz, 1H), 8.61-8.58 (m, 2H), 8.34 (d, J=3.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CO.[OH-].[Li+].Cl>C1COCC1>[CH:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:15])=[O:2])=[CH:7][CH:8]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)COc1ccc(C2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C2CC2)cc1
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of (4-cyclopropyl-phenoxy)-acetic acid methyl ester (1.29 g, 6.27 mmol) in mixed solvent (10 mL, MeOH: THF=1:1) was added 1N lithium hydroxide solution (5 mL). After stirring for 6 hours, the reaction mixture was acidified with aqueous 2N HCl and subsequently extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil (1.18 g, 98%).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[N:11]=[CH:10][C:9]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=O)=[CH:25][CH:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN([C:57](=[N+](C)C)[O:58][N:59]1[C:63]2=NC=CC=C2N=N1)C>CN(C=O)C.CCOC(C)=O>[CH2:17]([NH:16][C:15](=[O:19])[NH:14][C:12]1[CH:13]=[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([N:59]([O:58][CH3:57])[CH3:63])=[O:33])=[CH:27][CH:28]=2)=[O:21])=[CH:10][N:11]=1)[CH3:18]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)O)cc2)cn1
Agent: CN(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)N(C)OC)cc2)cn1
Temperature: 25 °C
Yield: 51 %

Procedure:
3-[4-[[4-anilino-6-(ethylcarbamoylamino)pyridine-3-carbonyl]amino]phenyl]propanoic acid (Compound 78) (14.5 mg, 0.032 mmol) and dimethyl hydroxylamine (3.8 mg, 0.039 mmol) were dissolved in DMF (1 mL) and the DIPEA (17 μL, 0.098 mmol) added, followed by [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (15 mg, 0.039 mmol). The mixture was stirred at RT. After 1 h the mixture was diluted with EtOAc and evaporated to dryness. The residue was dissolved in DCM and applied to a silica column, eluting with MeOH/DCM, to afford Compound 123 (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:17][CH3:18]
Reactant: CCCOC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared by following General Procedure AO above using n-propanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]([CH:8]1[CH2:10][CH:9]1[C:11]#[N:12])=[O:7].ClCCl>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[CH:6]([OH:7])[CH:8]1[CH2:10][CH:9]1[C:11]#[N:12]
Reactant: N#CC1CC1C(=O)c1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#CC1CC1C(O)c1ccc(F)cc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
409 mg (10.8 mmol) of sodium borohydride were added to 2.20 g (9.84 mmol) of the compound from Example 127A in 180 ml of ethanol and 60 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was added to dichloromethane, the phases were separated, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 1.52 g (69% of theory) of a mixture of the diastereomers of the title compound.