Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-].[O:14]1CCO[CH:15]1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC.Cl>ClCCl.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:19]/[CH:15]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C/C=C/c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-quinolinecarboxaldehyde (1.58 g, 10.05 mmol, prepared as described in U.S. Pat. No. 5,559,256), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 5 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Chromatography (SiO2, 1:1 hexane/ethyl acetate+0.2% triethylamine) provided a yellow solid that was partioned between ethyl acetate (20 mL) and 10% HCl (15 mL). The aqueous layer was washed with ethyl acetate (2×20 mL) and then made basic with 10% NaOH. The precipitated solids were collected by filtration, washed with water, and dried in vacuo to give 1.20 g (65%) of the title compound as a light yellow solid. MS 184 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([S:17][CH3:18])=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1.[OH:21]O.O>C(O)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([S:17]([CH3:18])=[O:21])=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1
Reactant: CSc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 35 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a slurry of 3-amino-5-chloro-4-methyl-6-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (7.5 g, 22.87 mmol) in glacial acetic acid (75 ml) is added a solution of 30% hydrogen peroxide in water (2.85 ml, 25.16 mmol). The mixture is stirred at 35° C. for 16 hour, cooled to room temperature, and poured over water (300 ml). A bright yellow precipitate is formed. The mixture is stirred at 0° C. for 1 hour then the solid is collected by filtration and dried under vacuum at 60° C. for 3 hours to afford the title compound as a bright yellow solid (5.58 g, 71%). Mass (m/z): 344.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A mixture of methyl 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (2.00 g), 1N aqueous sodium hydroxide solution (18.6 mL), tetrahydrofuran (30 mL) and methanol (20 mL) was stirred at room temperature for 2 hrs, and at 50-60° C. for 1 hr. The reaction mixture was acidified by adding 1N hydrochloric acid and concentrated. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was filtered with diisopropyl ether to give 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoic acid as a white solid (1.73 g, yield 85%). Recrystallization from ethyl acetate-diisopropyl ether gave needle crystals. melting point: 190-191° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(C)cc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
108 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(4-methoxyphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[C:25]([C:29]3[N:30]=[CH:31][S:32][CH:33]=3)=[CH:24][C:23]=2[CH2:34][CH3:35])[C:12]=1[CH2:36][CH2:37][CH3:38].[OH-].[Li+]>CO>[CH2:34]([C:23]1[CH:24]=[C:25]([C:29]2[N:30]=[CH:31][S:32][CH:33]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:36][CH2:37][CH3:38])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:39])=[O:2])[CH3:35]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (130 mg, 0.236 mmol) in methanol (4 mL) was treated with 1 M lithium hydroxide solution at 60° C. for 3 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with water. The solution was adjusted to pH ˜4 and extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a minimum of methylene chloride and hexane was added until the solution became cloudy. The mixture was concentrated slowly in vacuo to give 96 mg (76%) of the title compound. 1H NMR (CDCl3) δ 8.90 (s, 1H), 8.23 (dd, J=8, 1 Hz, 1H), 7.41 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.82 (d, J=8 Hz, 1H), 6.71 (d, J=3 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.54 (s, 1H), 4.25 (t, J=6 Hz, 2H), 4.22 (t, J=6 Hz, 2H), 2.59 (m, 4H), 2.35 (quintet, J=6 Hz, 2H), 1.50 (hextet, J=8 Hz, 2H), 1.19 (t, J=7 Hz, 3H), 0.88 (t, J=8 Hz, 3H); TOF MS ES+ exact mass calculated for C30H32NO6S (p+1): m/z=534.1950. Found: 534.1957. IR (CHCl3, cm−1) 2965, 1738, 1454. Anal. Calcd for C30H31NO6S: C, 67.52; H, 5.86; N. 2.62. Found: C, 67.19; H, 5.72; N, 2.53.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([C:18]#[N:19])[S:16][CH:17]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([C:18]#[N:19])[S:16][CH:17]=3)=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3csc(C#N)c3)cc21
Yield: 35.4 %

Procedure:
A mixture of 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile (0.23 g, 0.8 mmol) and Lawesson's reagent (0.38 g, 0.96 mmol) in anhydrous o-xylene was heated to reflux under nitrogen for 3 hours. The solvent was removed in vacuo and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/3:1) to afford the title compound as a yellow solid (85 mg, 35%): mp 242-243° C.; 1H-NMR (DMSO-d6) δ 12.22 (s, 1H, D2O exchangeable), 8.50 (d, 1H, J=1.2 Hz), 8.37 (d, 1H, J=1.0 Hz), 7.71 (m, 2H), 7.09 (d, 1H, J=8.0 Hz), 1.69 (s, 6H); MS (APCI) m/z 301 ([M+H]+, 100%); Anal. Calcd. For C15H12N2OS2: C, 59.97; H, 4.03; N, 9.33. Found: C, 59.67; H, 3.85; N, 9.14.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][NH:24][CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:38][CH:39]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(NC(=O)c4ccc(C(C)(C)O)cc4)nc4ccnn34)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)CNCC4)n3nccc3n2)cc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
tert-Butyl 7-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from Step A was dissolved in CH2Cl2 (2 ml). Trifluoroacetic acid (2 ml) was then added at 0° C. The mixture was stirred for 30 minutes at that temperature before being concentrated in vacuo. Residual trifluoroacetic acid was removed azeotropically with toluene twice. The residue was then dissolved in acetonitrile before being purified by preparatory HPLC (20-30% MeCN/H2O gradient+0.01% TFA) to give the titled compound as a white powder (50 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.30 (s, 1 H), 9.14 (br. s., 2 H), 8.21 (d, J=2.5 Hz, 1 H), 8.07 (s, 1 H), 8.05-8.01 (m, 2 H), 8.00-7.95 (m, 1 H), 7.65-7.60 (m, 2 H), 7.50 (d, J=8.1 Hz, 1 H), 6.60 (d, J=2.3 Hz, 1 H), 4.47-4.40 (m, 2 H), 3.47 (br. s., 2 H), 3.13 (t, J=6.2 Hz, 2 H), 1.46 (s, 6 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:27][NH2:28]>CO>[CH3:27][NH:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Solvent: CO
Product: CNc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Temperature: 50 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (19 mg, 0.05 mmol) was added to methyl amine in MeOH (1N, 2 mL) in a sealed bottle and heated to 50° C. for 2 days. The reaction crude were cooled down to r.t. and concentrated on rotavapor. The crude mixture was purified by preparative TLC with 10% methanol: dichloromethane to yield title compound.
Reaction SMILES: C(O[C:6](=[O:32])[NH:7][CH2:8][CH2:9][N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(C)(C)C.Cl.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:46][C:47]1[C:56]2[C:51](=[N:52][C:53]([CH3:57])=[CH:54][CH:55]=2)[N:50]=[CH:49][CH:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CC(O)=O.O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:11]2[C:12]3[C:17](=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:18][CH2:19][N:10]2[CH2:9][CH2:8][NH:7][C:6]([NH:46][C:47]2[C:56]3[C:51](=[N:52][C:53]([CH3:57])=[CH:54][CH:55]=3)[N:50]=[CH:49][CH:48]=2)=[O:32])=[CH:26][CH:27]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc2c(N)ccnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)Nc1ccnc3nc(C)ccc13)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of {2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH (1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture is partitioned with CHCl3 (20 mL) and 1 N NaOH (15 mL). The organic phase is evaporated. The residue is taken up in DMSO (2 mL) and treated with CDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred at rt for 3 h, and then 4-amino-7-methyl-[1,8]-naphthyridine (example C5, 0.19 g, 0.6 mmol) is added. To the resulting solution is added in a single portion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reaction mixture is stirred at rt for 30 min, then H2O (0.4 mL) is added. The reaction mixture is evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CCNC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCCC3)CC2)nc1N
Temperature: 90 °C
Yield: 45.2 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (25 mg, 0.051 mmol, Example 272), potassium iodide (30 mg, 0.18 mmol), and pyrollidine (400 mg, 5.6 mmol) in dioxane (8 mL) was heated at 90° C. under nitrogen for 14 hours. The resulting solution was concentrated to ˜1 mL and triturated with water. Solids were filtered and dissolved in methylene chloride. After washing with water, the organic layer was separated and dried (Na2SO4). The product was purified by trituration with tetrahydrofuran/ethyl ether and filtered to give [4-amino-2-[1-(3-pyrrolidin-1-yl-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (12 mg, 40% yield). HRMS, observed: 521.2343; Calcd for (M+H)+: 521.2341
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH3:30]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:28][O:29][CH3:30])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-bromo-3-nitropyridin-2-yl)phenol (280 mg, 0.95 mmol) and DIPEA (360 mmg, 2.85 mmol) in 5 mL of dry DCM at 0° C. was added dropwise chloro(methoxy)methane (210 mg, 1.9 mmol). The reaction was warmed to rt and stifling was continued for 3 h and the diluted with EtOAc (30 mL), washed with water (3×30 mL) and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by silica chromatography (EtOAc in hexane, 5% to 35%) to afford 5-bromo-2-(4-(methoxymethoxy)phenyl)-3-nitropyridine as a yellow wax (260 mg, 80%). MS (ESI) m/z [M+H]+339, 341.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]2[NH:41][CH:40]([C:42](O)=[O:43])[CH2:39][S:38]2)[CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:42]([CH:40]2[CH2:39][S:38][CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[NH:41]2)=[O:43])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCNCCCc1ccccc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCNCCCc1ccccc1)C1CSC(c2cccnc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 200 mg of 3-phenylpropylethylenediamine and 81 mg of N-methylmorpholine in 5 ml of dimethylformamide, there were added in sequence 120 mg of 1-hydroxybenzotriazole, 180 mg of dicyclohexylcarbondiimide and 170 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. After addition of 0.5N aqueous sodium hydroxide, the residue was extracted with ethyl acetate. The organic layer was extracted with 1N hydrochloric acid, and the aqueous layer was adjusted to pH 10 with potassium carbonate and extracted again with ethyl acetate The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to alumina column chromatography (20 g). Elution with methanol-ethyl acetate (1:10) gave 160 mg of N-(3-phenylpropylaminoethyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. The NMR and MS data for this compound were in agreement with those given in Examples 115.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: COc1ccc(CCl)cc1
Reactant: CON(C)C(=O)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc(F)c2C(=O)N(C)OC)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide (4.320 g, 21.689 mmol) in acetone (50 mL) were added 4-methoxy benzylchloride (3.74 g, 23.858 mmol), potassium carbonate (4.50 g, 32.534 mmol), and potassium iodide (360 mg, 2.169 mmol). The mixture was stirred at reflux for 15 hrs. After cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 2-fluoro-N-methoxy-6-[(4-methoxybenzyl)oxy]-N-methylbenzamide as a pale yellow oil (6.926 g, yield; quant.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[NH2:5].CCCCC.O.[CH:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[N:5]=[CH:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C=O
Reactant: CNC(=O)[C@@H](N)CCSC
Solvent: O
Solvent: CCCCC
Product: CNC(=O)[C@H](CCSC)N=CC(C)(C)C

Procedure:
There were added to 40.0 grams (247 mmoles) of (S)-methionine mono-methylamide dissolved in 100 ml of n-pentane 27.5 ml (250 mmoles) of pivalaldehyde. The reaction mixture was boiled on the water separator until the formation of water ended (3 hours). The solvent was removed under reduced pressure and there remained behind 52.2 grams (92% of theory) of (S)-N-(2', 2'- dimethylpropylidene)-methionine mono-methylamide which was further processed without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[C:30]2([CH2:33][O:32][CH2:31]2)[C:10]2([CH2:14][O:13][C:12]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[O:3]1.Br[C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][N:46]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CO.C(Cl)(Cl)Cl.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>[CH3:52][O:51][C:49]1[CH:48]=[CH:47][N:46]=[C:45]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:1])([CH3:43])[C:30]2([CH2:31][O:32][CH2:33]2)[C:10]23[CH2:14][O:13][C:12]([NH2:15])=[N:11]2)[CH:50]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OC(C)(C)C21COC1
Reactant: COc1ccnc(Br)c1
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: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccnc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C(C)(C)O3)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of di-tert-butyl [2′,2′-dimethyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (282 mg, 0.470 mmol), 2-bromo-4-methoxypyridine (221 mg, 1.17 mmol), tetrakis(triphenylphosphine)palladium(0) (271 mg, 0.235 mmol) and Na2CO3 (149 mg, 1.41 mmol) in dioxane-water (4:1, 5.6 mL) was stirred for 8 hours at 100° C. The mixture was diluted with MeOH—CHCl3 (1:9) and washed with water, then the organic layer was dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure. To the residue were added toluene (2.8 mL) and silica gel (neutral; 846 mg), and the mixture was stirred for 3 hours at 120° C. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) afforded 6′-(4-methoxypyridin-2-yl)-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (146 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:8]=1[C:9]#[N:10]>>[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:4][CH2:3][C@@H:2]([NH2:1])[CH3:5])[C:8]=1[C:9]#[N:10]
Reactant: N#Cc1c(N)cccc1F
Reactant: C[C@H](N)CO
Product: C[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-aminopropan-1-ol and 2-amino-6-fluoro-benzonitrile as brown solid (73%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H), 5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H). MS 192 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Br[C@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:21]>C(#N)C>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:21])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCC

Procedure:
Introduce 123 g of ethyl (2S)-2-aminopentanoate, 160 ml of triethylamine and 160 ml of acetonitrile into a reactor, and then bring the mixture to 60° C., slowly add the solution obtained in Step A and reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield benzyl (2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate.