Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.Cl>C(C(C)=O)C(C)C>[I:9][C:10]1[CH:11]=[C:12]([S:16]([NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccnc1N
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Agent: Cl
Solvent: CC(=O)CC(C)C
Product: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Reaction time: 8 h

Procedure:
32.4 g 3-methyl-2-pyridinamine (32.4 g, 0.3 mol) was dissolved in isobutylmethylketone (200 ml) and 3-iodo-benzenesulfonyl chloride (30.2 g, 0.1 mol) was added with stirring. The solution was kept at 40° C. for 8 h and then added to dilute hydrochloric acid. The precipitate was filtered off and the organic phase was separated and evaporated. The residue was combined with the first solid material and recrystallized from ethanol. The crystals were dissolved in 1M sodium hydroxide (about 200? ml) and extracted with isobutylmethylketone (3×100 ml). The aqueous phase was partially evaporated to remove isobutylmethylketone residues. Ethanol (100? ml) was added and the solution acidified with acetic acid. The precipitate was filtered off, washed with water and dried. Yield 23 g, 61%.
Reaction SMILES: [I:1]Cl.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(=O)(O)[O-].[Na+]>O.Cl>[I:1][C:14]1[C:8]2[S:7][C:6]([CH2:5][O:4][CH3:3])=[N:10][C:9]=2[CH:11]=[CH:12][C:13]=1[NH2:15]
Reactant: COCc1nc2ccc(N)cc2s1
Reactant: ClI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1nc2ccc(N)c(I)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of iodine monochloride in water (1.5 mL) and 12 N hydrochloric acid (0.46 mL) was added 2-methoxymethyl-benzothiazol-6-ylamine (0.5 g, 2.57 mmol) in water (3 mL) and 12 N hydrochloric acid (0.23 mL). The reaction mixture stirred at RT for 2 h and was then neutralized with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (20 to 30% ethyl acetate:hexanes) afforded 800 mg (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, J=8.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 4.77 (s, 2H), 4.23 (br. s, 2H), 3.53 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccccc1Oc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 2-phenoxybenzoic acid (10.00 g, 46.7 mmol) in THF (250 mL) was added dropwise borane.dimethylsulfide (9.8 mL of a 10.0M solution, 98 mmol). Upon completion of addition, the reaction was stirred for 15 hrs. It was then quenched with aqueous 10% HCl (250 mL) and extracted with ethylacetate (3×250 mL). The organics were combined, dried with MgSO4 and concentrated to afford crude 2-phenoxybenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Li])CCC.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:24][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1
Reactant: Fc1ccccc1I
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2F)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of 2-fluoro-1-Iodobenzene (11.1 g, 50.0 mmol) in 50 mL THF, cooled to -78° C. under argon, was added n-butyllithium (20.0 mL 2.5M in hexane, 50.0 mmol). The solution was stirred 10 min. at -78° C., and a solution of 1,4-cyclohexanedione mono-ethylene ketal (7.81 g, 50.0 mmol) in 50 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized from dichloromethane/hexane to give 8-(2-Fluoro-phenyl)-1,4-dioxa-spiro-[4.5]decan-8-ol (3.8 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:17]([NH:20][C:21](=[O:38])[CH:22]=[CH:23][CH2:24][N:25]([CH2:30][C:31]([O:33][C:34]([CH3:37])(C)[CH3:35])=[O:32])C[C@@H](O)C)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:17]([NH:20][C:21](=[O:38])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:35][C@H:34]([CH3:37])[O:33][C:31](=[O:32])[CH2:30]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1

Procedure:
A mixture of 700 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline and 228 mg of p-toluenesulphonic acid hydrate in 20 ml of acetonitrile is refluxed for five hours. Then a further 200 mg of p-toluenesulphonic acid hydrate are added and the mixture is again refluxed for five hours. For working up the reaction mixture is evaporated to dryness. The flask residue is distributed between ethyl acetate and saturated sodium carbonate solution. The organic phase is separated off, washed with saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The oily residue is brought to crystallisation by stirring with 15 ml diethyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25](O)=[O:26])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1)#[N:2].ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[O:54]=[C:52]1[NH:51][CH2:50][CH2:47][N:49]([C:25]([C:16]2[CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([CH:8]=[C:7]([O:9][C:10]([F:12])([F:13])[F:11])[CH:6]=3)[C:1]#[N:2])[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)=[O:26])[CH2:53]1
Reactant: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
30 mg (0.08 mmol) of the compound of Example 58A is reacted analogously to the synthesis of the compound of Example 1 with 9 mg (0.09 mmol) of 2-oxopiperazine. 30 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:20])[C:16](OC)=[O:17])=[CH:3][CH:2]=1.C1COCC1.[CH3:32][NH2:33].Cl>CO.O>[CH3:32][NH:33][C:16](=[O:17])[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][O:7][C:4]1[CH:5]=[CH:6][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:2][CH:3]=1)=[O:20]
Reactant: COC(=O)C(=O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)C(=O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Yield: 81.9 %

Procedure:
To methyl 2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-oxoacetate (3.46 g, 0.01 mol), added were anhydrous methanol (10 ml), dry THF (10 ml) and a 40% solution (2.33 g) of methyl amine (0.03 mol) in methanol, and the reaction mixture was stirred at room temperature for 2 hour. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then adjusted to below PH 2 by addition of conc. HCl and extracted with ethyl acetate (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals (3.42 g; yield, 99.1%) were recrystallized from ethyl acetate/n-hexane to give N-methyl-2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-oxoacetamide (2.83 g) as colorless crystals (m.p.: 144°-145° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][NH:13][C:12]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:27][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:26]
Reactant: O=C(OCc1ccccc1)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
A mixture of 25 g of benzyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 29.3 g of anhydrous potassium carbonate, 50 g of methyl iodide and 200 ml of acetone is vigorously stirred at room temperature for 5 days. The mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is collected therefrom. The ethyl acetate solution is dried and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography and then triturated with ether. 18.2 g of benzyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 60.7%
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)=[O:5].ClC1C=CC([N+]([O-])=O)=CC=1C(C1NC(C(Cl)=O)=CC=1)=O.C(Cl)(=O)C(Cl)=O.[N:47]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[N:47]1([CH2:53][CH2:54][NH:55][C:11]([C:9]2[NH:10][C:6]([C:4](=[O:5])[C:3]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=3[Cl:1])=[CH:7][CH:8]=2)=[O:13])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: O=C(O)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Reactant: NCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Product: O=C(NCCN1CCOCC1)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1

Procedure:
5-(2-Chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (200 mg) was converted to 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carbonyl chloride using oxalyl chloride at room temperature for one hour. It was then condensed with 2-morpholin-4-yl-ethylamine and TEA for one hour at room temperature to give 120 mg of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.O.NN.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>C1COCC1.O.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>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2ccc(CCO)cc2)c1

Procedure:
20 g (99 mmol) of 2-(4-bromophenyl)ethanol, 20 g (72 mmol) of sodium metaborate octahydrate and 2.0 g (2.8 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 30 ml of THF and 120 ml of water, and, after addition of 0.03 ml of hydrazine hydrate, a solution of 15.5 g (85 mmol) of 3,5-dimethoxybenzeneboronic acid in 60 ml of THF is added dropwise. The batch is heated under reflux overnight and subsequently extracted four times with dichloromethane. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is chromatographed on silica gel with heptane/ethyl acetate (2:1), giving 2-(3′,5′-dimethoxybiphenyl-4-yl)ethanol as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[N:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-6 using tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 6-chloropyridin-3-ol (0.10 g, 54%); MS: 271 (M−56).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: COc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[C:7]([O:17][CH3:18])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)[CH:11]=1)=[O:4].N[C@@H:27]([CH2:43]C1C=CC=CC=1)[C:28]([NH:30][C:31]1C(=O)NC=C(C2C=NNC=2)C=1)=O.[S:50]1C=C(C=O)N=C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:18][O:17][C:7]1[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:43][C:27]2[S:50][CH:31]=[N:30][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2cn[nH]c2)c[nH]c1=O
Reactant: O=Cc1cscn1
Reactant: COc1ncc(-c2cn[nH]c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ncc(-c2cn[nH]c2)cc1NC(=O)[C@H](Cc1ccccc1)NCc1cncs1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of a 1:9 mixture of (2S)-2-amino-N-(2-methoxy-5-(1H-pyrazol-4-yl)pyridin-3-yl)-3-phenylpropanamide 15.1.D and (S)-2-amino-N-(2-oxo-5-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-3-phenylpropanamide (90 mg, 0.28 mmol) in DCM (1 mL) was added thiazole-4-carbaldehyde (26 mg, 0.28 mmol) and was then stirred for 1 hour. Sodium triacetoxyborohydride (170 mg, 0.82 mmol) and acetic acid (16 μL, 0.28 mmol) was then added, the mixture was stirred for an additional 1 hour at room temperature, concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (2S)—N-(2-methoxy-5-(1H-pyrazol-4-yl)pyridin-3-yl)-3-phenyl-2-(thiazol-5-ylmethylamino)propanamide 15.1 (5.7 mg, 57%) as a white solid. LCMS ESI (pos.) m/e: 435.1 (M+1): 1H NMR (500 MHz, MeOH-D4) δ ppm 9.13 (d, J=1.83 Hz, 1H), 8.50 (d, J=1.83 Hz, 1H), 8.15 (d, J=1.83 Hz, 1H), 7.94 (s, 2H), 7.80 (d, J=1.83 Hz, 1H), 7.25-7.39 (m, 5H), 4.46-4.56 (m, 3H), 3.91 (s, 3H), 3.41 (dd, J=13.43, 6.10 Hz, 1H), 3.24 (dd, J=13.43, 9.16 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:19]([O:16][C:15]1[CH:17]=[CH:18][C:10]([CH:9]=[O:8])=[CH:11][C:12]=1[O:13][CH3:14])(=[O:21])[CH3:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Triethylamine (2.8 liters, 20.1 moles) was added dropwise to a solution of vanillin (2.00 kg., 13.15 moles) and acetic anhydride (2.6 liters, 27.5 moles) in methylene chloride (11.3 liters) maintaining temperature below 25° C. After adding 4-dimethylaminopyridine (20 g.) the solution was stirred at room temperature for 30 minutes. The reaction mixture was washed twice with water, followed by 20% (w/w) hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane (15 liters) was added slowly while removing remaining methylene chloride. After cooling, 2.45 kg. (96% yield) product was filtered off. Recrystallization of a small sample from anhydrous ether gave the acetate as fine yellow needles, M.P. 76°-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:16]1[CH:20]=[C:19]([CH:21]=O)[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C(O)=O>O>[CH2:37]([O:36][C:30](=[O:35])[CH:31]=[CH:21][C:19]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH:20]=1)[CH3:38]
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)c1cc(C=O)on1
Reactant: CCOC(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C=Cc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Temperature: 55 °C
Yield: 95.5 %

Procedure:
A stirred mixture of [1-(5-formyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 1.3 mmol), pyridine (10 ml) and ethyl hydrogen malonate (255 mg, 1.9 mmol) was warmed to 55° C. After 2 days the mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organics were washed with 1N HCl, water, and brine; dried over NaSO4, filtered and concentrated under reduced pressure to give 480 mg of a yellow oil. Purification by Flash 40(small) chromatography eluting with 1:3 EtOAc/hexane gave 220 mg of the title compound as a light yellow oil. MS [M+1]+ 387.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O.O1CCCC1>[CH3:19][O:18][C:16]([NH:1][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:17]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
A solution of D-phenylalanine (25.00 g, 0.151 mol) and sodium hydroxide (6.05 g, 0.151 mol) in water (170 ml) and tetrahydrofuran (225 ml) was cooled to −15° C., and a solution of methyl chloroformate (18.6 g, 0.197 mol) in tetrahydrofuran (50 ml) was added dropwise. When the addition was ˜half complete, a solution of sodium hydroxide (9.10 g, 0.227 mol) in water (20 ml) was also added dropwise. When the additions were complete, the mixture was stirred at room temperature for an additional 2 hours and acid fixed with 10% hydrochloric acid. The acid was extracted twice with diethylether, and the extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a clear oil (38.38 g). HPLC 6.01 min (78.9%), 7.32 min (5.0%), 8.29 min (10.8%), 8.42 min (0.5%), 9.95 min (1.2%), 10.27 min (2.8%), 11.92 min (0.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:18])[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred solution of 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propionitrile (3.51 g, 13.2 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 46.4 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 30 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6N aqueous NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 27.7 mL, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 3.10 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[CH:21]=1)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][CH2:17][N:16]([C:1](=[O:3])[CH3:2])[C:15]=2[CH:21]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Acetic anhydride (1.00 mL, 10.6 mmol;) was added to a solution of 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.580 g, 2.99 mmol), 4-Dimethylaminopyridine (20 mg, 0.1 mmol; Acros) and Triethylamine (1.0 mL, 7.2 mmol) in Acetonitrile (10 mL; Acros). The reaction was stirred under an atmosphere of Nitrogen overnight. Conversion was moderate, so the mixture was heated at 50° C. for the weekend. The solution was conc. in vacuo, diluted with 25 mL EtOAc then washed with 1N HCl (10 mL), satd. sodium bicarbonate (10 mL) and brine (10 mL). After drying over sodium sulfate, the solution was conc. and the residue chromatographed (ISCO, 80 g SiO2, 0-65% EtOAc:Hex) to afford 1-(2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone as light yellow solids (522 mg, 74%). Mixture of rotamers in 1H-NMR, resulting in very broad signals for the aliphatic methylenes. 13C-NMR (CDCl3): 169.8, 160.3, 142.7, 134.3, 124.8, 124.6, 122.6, 71.1, 45.0, 28.0, 22.4