Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH3:32])[C:16]=2[CH:33]=1.[CH2:40]=[O:41].O>C1COCC1>[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH2:32][CH2:40][OH:41])[C:16]=2[CH:33]=1
Reactant: C=O
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc([N+](=O)[O-])c3)c(CCO)c2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
LiHMDS (57.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at −78° C. to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (20.0 g, 48.0 mmol) in anhydrous THF (250 mL), and the reaction mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. Paraformaldehyde (2.88 g, 96.0 mmol) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was obtained by vacuum concentration, and it was washed with ethyl acetate to yield the title compound (18.5 g, 86%) as a white powder.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[O:24][N:23]=[C:22]([NH2:25])[CH:21]=1>O1CCCC1>[CH3:19][C:20]1[O:24][N:23]=[C:22]([NH:25][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:21]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(N)no1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccccc32)no1

Procedure:
The named compound is prepared by substituting 5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gins.) is reacted with 0.1228 gms. 5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: CN1CCNCC1
Reactant: O=C(Nc1c[nH]nc1-c1nc2c(C(=O)O)cccc2[nH]1)c1c(F)cccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid (50 mg, 0.13 mmol), N-methylpiperazine (20 μl, 0.18 mmol), EDC (30 mg, 0.15 mmol) and HOBt (22 mg, 0.15 mmol) in DMF (5 ml) was stirred at ambient temperature for 18 h. The mixture was reduced in vacuo and the residue purified by flash column chromatography [SiO2, CH2Cl2/MeOH (95:5, 90:10)] to give 2,6-difluoro-N-{3-[4-(4-methyl-piperazine-1-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (14 mg) as a cream solid. (LC/MS: Rt 2.21, [M+H]+ 466).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)OC)#[N:2].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[N:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: COC(=NC#N)c1ccc(C#N)cc1
Reactant: NCCc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: N#CNC(=NCCc1ccccc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-4-cyanobenzenecarboximidate (0.37 g, 2.0 mmol) was suspended in methanol (4 ml), and 2-phenylethylamine (0.25 g, 2.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, methanol (6 ml) and diethyl ether (10 ml) were added to the reaction solution, and deposited crystals were collected by filtration to give the title compound (0.51 g, 1.87 mmol, yield: 94%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]([N:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[CH3:17])=[O:15]>>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CN(C(=O)CN)C1CCN(Cc2ccccc2)CC1
Product: Cc1cc([N+](=O)[O-])cnc1NCC(=O)N(C)C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized from 2-chloro-3-methyl-5-nitropyridine and 2-amino-N-(1-benzylpiperidine-4-yl)-N-methylacetamide in the same manner as in Example 10.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 55 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using morpholine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 132 mg, 55%) which was obtained as an off-white solid. MS: m/e=419.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:18](=[O:17])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OC(=O)c4ccccc4)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 23 h
Yield: 163.4 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (0.18 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (30 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (252 mg, 82%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.21 (d, J=8.0 Hz, 2H), 8.07 (d, J=6.4 Hz, 2H), 8.00 (dm, J=8.4 Hz, 2H), 7.68 (t, J=6.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.35 (dm, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 5.82 (pentet, J=6.3 Hz, 1H), 5.37 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.6 Hz, 1H), 2.34 (s, 3H), 1.51 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Br:11])[CH:5]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]=1[CH2:10][Br:20]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Br)c1
Yield: 95.5 %

Procedure:
A mixture of methyl-3-bromo-4-methylbenzoate (40 g, 0.17 mol), NBS (34 g, 0.19 mol) and benzoylperoxide (4.0 g) in CCl4 (500 mL) was refluxed for 6 h. The reaction mixture was cooled and filtered off the solid. The filtrate was concentrated under vacuum to give 2-bromo-4-methoxycarbonylbenzyl bromide (50 g, 93%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([N:18]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])[C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(N(CC(=O)OC(C)(C)C)C(=O)c2cccnc2SCc2ccnc(N)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A solution of 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (the free base of Compound No. 3-1, 50 mg, 0.14 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added dropwise to a suspension of 60% sodium hydride (13 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) under ice-cooling, and the mixture was stirred for 5 minutes. Bromoacetic acid tert-butyl ester (22 μL, 0.15 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes at room temperature. The mixture was poured into ice water (15 mL), and the whole was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 45 mg of the target compound as a colorless amorphous. (Yield 69%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.I[CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][CH2:70]1>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:68][CH:69]2[CH2:73][CH2:72][CH2:71][CH2:70]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3
Reactant: ICC1CCCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(CC2CCCC2)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3-chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]-dioxino-[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (24 mg) was reacted with iodomethyl cyclopentane (11 mg) according to General Procedure T to obtain (S)-2-({(S)-7-[2-(Acetyl-cyclopentylmethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3-chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound. LCMS: (m/z) 972.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[C:5](=[O:25])[CH2:6][CH2:7][CH2:8]2.[I-].[K+].O>C(O)=O>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[C:5](=[O:25])[CH2:6][CH2:7][CH2:8]2
Reactant: CCCc1c2c(c(OC)c3c(=O)cc(C(=O)OC)oc13)C(=O)CCC2
Agent: [I-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)OC)oc13)C(=O)CCC2
Yield: 109 %

Procedure:
Methyl 6,7,8,9-tetrahydro-5-methoxy-4,6-dioxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (172 mg; 0.5 mmole) in formic acid (5 ml) was heated on a steam bath with ground potassium iodide (800 mg; 4.8 mmole) for 1 hour. The mixture was poured into water and extracted with ethylacetate (3×). The organic fractions were washed with water and dried (sodium sulphate) to yield a brown oil (180 mg) which crystallised on trituration with ethanol. The solid was filtered off and washed with a little ether to give the title compound as a yellow powder (110 mg; 67%) mp 200° (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: COc1ccc(CN)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2c(F)cc(C#N)cc2F)cc1
Yield: 100 %

Procedure:
To acetonitrile solution (500 ml) of 3,4,5-trifluoro-benzonitrile (15.0 g, 95.5 mmol), N-ethyldiisopropylamine (33.3 ml, 191 mmol) and 4-methoxy-benzylamine (24.9 ml, 191 mmol) were added, followed by refluxing for 21 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (500 ml), which was washed with saturated aqueous sodium chloride solution (200 ml). After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane), to obtain the desired compound (26.2 g, quant.).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine,whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.1 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[CH:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)O[PH](=O)CC1=CC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)O[PH](=O)CC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of isopropyl (3-hydroxycyclopentenyl)methylphosphinate (3) (3.5 g, 17.2 mmol) in anhydrous DMF (60 cm3) was treated with t-butyldimethylsilyl chloride (2.85 g, 18.9 mmol), triethylamine (3.6 g, 34.3 mmol) and DMAP (250 mg). The reaction mixture was stirred at room temperature for 16 h, after which time the solvent was removed in vacuo. The residue was partitioned between DCM (50 cm3) and water (30 cm3) and the aqueous layer was further extracted with DCM (3×20 cm3). The combined organic layers were washed with water (2×30 cm3) and brine (40 cm3), dried over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by short column vacuum chromatography on silica gel (5% ethanol/ethyl acetate) to yield the title compound (4) as a colourless oil (4.62 g, 85%): 1H NMR (300 MHz, CDCl3) δ 0.065 and 0.067 (6H, 2×s), 0.870 and 0.874 (9H, 2×s), 1.22 and 1.24 (3H, 2×d, J=6.3 and 6.3 Hz, OCHCH3), 1.31 and 1.33 (3H, 2×d, J=6.0 and 6.0 Hz, OCHCH3), 1.45 and 1.49 (3H, 2×d, J=14.4 and 14.4 Hz, PCH3), 1.69-1.83 (1H, m, C(5)—H), 2.24-2.46 (2H, m, C(5)—H′ and C(4)—H), 2.54-2.68 (1H, m, C(4)—H′), 4.55 (1H, m, OCHCH3), 4.95 (1H, m, C(3)—H), 6.46 (1H, m, C(2)—H), 13 C NMR (75.46 MHz, CDCl3) δ −4.81 and −4.75 (Si(CH3)2, 2×s), 14.0 and 14.19 (PCH3, d, JPC=101.3 and 101.8 Hz), 18.07 and 18.10 (SiC(CH3)3, 2×s), 23.90 and 23.96 (POCCH3, 2×d, 3JPOCC=4.8 Hz), 24.43 (POCCH3, overlapping d, 3JPOCC=3.3 Hz), 25.76 (SiC(CH3)3, br. s), 31.34 (C(4), d, 3JPC=11.5 Hz), 34.42 and 34.55 (C(5), 2×d, 2JPC=9.5 Hz), 68.95 and 68.99 (POCHCH3, d, 2JPOC=6.5 and 5.9 Hz), 77.98 and 78.24 (C(3), d, 3JPC=6.9 and 6.7 Hz), 137.78 and 138.08 (C(2), d, JPC=125.0 and 125.6 Hz), 147.2 (C(1), d, J=10.7 Hz), 31P NMR (121 MHz, CDCl3) δ 38.1, 38.5, (ESI) 319.1869 (MH+-C15H32O3PSi requires 319.1858).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O.NN.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C1(C)C=CC=CC=1>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[NH2:3][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C(O)/C=C\C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.50 (s, 9H), 1.50-1.64 (m, 6H), 3.22 (m, 1H), 3.83 (br s, 1H), 6.02 (s, 2H), 6.86 (d, J=7.5 Hz, 1H), 7.68 (br s, 3H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH2:31])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[C:40]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH:31][C:49](=[O:50])[CH2:48][NH:47][C:45]([O:44][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:46])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)CNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 104.7 %

Procedure:
Triethylamine (1.13 mL), 1-hydroxybenzotriazole (1.04 g), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.56 g) were added to a solution of cis-4-amino-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D102 (C), 1.65 g) and N-tert-butoxycarbonylglycine (1.42 g) in dichloromethane (100 mL) at 0° C. The mixture was stirred at room temperature for 19 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (2.84 g) as a colorless foam.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13](O)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:65]([CH:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[CH:11][N:10]=1)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:66]=[N-:67]
Reactant: CCC(CC)C(O)c1nccn1Cc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutan-1-ol (1.78 g, 6.88 mmol) in THF (50 mL) at 0° C. was added triphenylphosphine (2.71 g, 10.3 mmol), diethyl azodicarboxylate (1.62 mL, 10.3 mmol) and diphenylphosphorylazide (2.22 mL, 10.3 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and extracted 2 times with 1N HCl. The aqueous layer was washed EtOAc, then basicified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, 100% CHCl3, then MeOH/CHCl3/Et3N, 1:98.5:0.5) to yield a pure oil in 30% yield.