Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH:11][C:19](=[O:21])[CH3:20])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccc(Cl)nn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution 6-chloroimidazo[1,2-b]pyridazin-3-amine and triethylamine (0.8 mL, 6.0 mmol) in DCM (25 mL) was added acetyl chloride dropwise and stirred at rt for overnight. The mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give not very pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide (500 mg, 95% yield). 60 mg of non-pure material was further purified by Prep HPLC (neutral) to give pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.35 Hz, 1H), 7.94 (s, 1H), 7.26 (d, J=9.35 Hz, 1H), 2.29 (s, 3H); LRMS (ESI) m/e 210.9 [(M+H)+, calcd for C8H8ClN4O 211.6].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:35])[F:36])=[O:34]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (927 mg, 4.19 mmol) and Et3N (645 μl, 4.63 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (633 μl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 62%) as a white crystalline powder. mp 178-180° C.; 1H-NMR (CDCl3) δ1.44 (s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12-7.18 (m, 3 H), 7.36-7.37 (m, 1 H), 7.49-7.53 (m, 2 H), 8.13-8.16 (m, 1 H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](CC(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].CN(C=O)C>ClCCl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
3.75 ml (7.5 mmoles) of a 2 M solution of oxalyl chloride in dichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of 4-nitrophenylacetic acid in a mixture composed of 10 ml of dichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, the solution is concentrated under vacuum. The yellow oil obtained is used without additional purification in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.CCOCC.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:31])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: N
Reactant: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: CCOCC
Solvent: CO
Product: NC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 100 mg, 0.28 mmol) was dissolved in a 7N solution of ammonia in MeOH (40 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. Et2O was added and the yellow precipitate was collected by filtration. DCM was added and the off white precipitate was isolated by filtration, this was repeated to yield the title compound as an off white solid (59 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.64 (d, J=1.6 Hz, 2H), 7.57-7.44 (m, 4H), 7.37 (dd, J=2.7, 9.0 Hz, 1H), 7.08-7.02 (m, 1H), 5.34 (s, 2H), 3.60 (s, 2H). [M+H]=327.2.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]2[S:22][C:23]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=2)[CH2:16]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[S:22][C:23]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=3)[CH2:16]2)=[O:11])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cn1
Reactant: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)N[C@@H]2CCCN(c3nc(C(N)=O)c(Nc4ccccn4)s3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 6-tert-butylnicotinic acid (23.5 mg, 131 μmol) and 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide (38 mg, 119 μmol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (35 μL, 200 μmol) followed by 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 161 μmol). After stirring at ambient temperature overnight under an atmosphere of argon the reaction was quenched by the addition of saturated aqueous ammonium chloride (2 mL), the mixture poured into water (5 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were washed with brine (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a yellow solid. The crude product was purified by chromatography using a 13 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo and the residue lyophilized from acetonitrile/water to give (R)-2-(3-(6-tert-butylnicotinamido)piperidin-1-yl)-5-(pyridin-2-ylamino)thiazole-4-carboxamide as a pale yellow solid (37.8 mg, 66%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(O)[CH2:31][CH2:32][OH:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:29][Si:2]([CH3:1])([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:31][CH2:32][OH:33])=[O:23])=[CH:26][CH:27]=1
Reactant: OCCCO
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1

Procedure:
A mixture of 2.2 g. of methyl 4-[14-(trimethylsilyl)tetradecylamino]benzoate, 280 mg. of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.I[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:22][CH:23]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 32.9 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (700 mg, 2.69 mmol) synthesized in Reference example 56 and 4-iodotoluene (1.76 g, 8.08 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 310 mg (yield 33%). Melting point was 150 to 151° C. (ethanol).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:27]([CH3:28])[CH3:26])=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25]
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 21.2 g. of the product of Example 4, containing 62% of 5-methyl-3-phenyl-6-(p-bromomethylphenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (0.0332 mole of bromo compound) and 7.2 g. (0.160 mole) dimethylamine in 300 ml. toluene is stirred overnight at room temperature. The mixture is filtered and the solid washed with toluene and the solvent evaporated in vacuo. The resulting solid is dissolved in methylene chloride and treated with 2N hydrochloric acid, the precipitate is then filtered, washed with water and ether. The solid is then dissolved in methylene chloride and 2N sodium dioxide and the organic phases separated and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 5-methyl-3-phenyl-6-(p-[dimethylaminomethyl]phenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; m.p. 159°-161° C.
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[F:20][C:21]1[CH:47]=[CH:46][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][NH:42]3)=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1>O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:15]([NH2:14])=[O:16])=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:46][CH:47]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mg of dimethylaminopyridine and 0.059 ml of trimethylsilyl isocyanate were added in order to a methylene chloride (1 ml) solution of 31.2 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>CN(C1C=CN=CC=1)C>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN(C)c1ccncc1
Product: C[C@@H](c1ccc(C#CC(C)(C)NC(=O)N(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and dimethylcarbamyl chloride with the addition of DMAP. LC-MS Method 1 tR=1.53 min, m/z=506, 448; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.48 (d, 3H), 1.71 (s, 6H), 2.10-2.40 (5H), 2.78 (m, 1H), 2.91 (s, 6H), 5.63 (q, 1H), 6.86 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1OC
Yield: 44.6 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3,4-dimethoxyphenylboronic acid (80 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification by Prep-TLC (silica gel) yielded 50 mg (44%) of 3-(3,4-dimethoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11].N1C=CC=CC=1.Cl>O>[C:1]([NH:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:33])([F:32])[F:34])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC[C@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H](NC(C)=O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C

Procedure:
10 ml of acetic anhydride and 6 g of 2-[(1S) 1-aminopropyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide of Example 8 were added dropwise with stirring to 60 ml of pyridine and stirring was maintained for 90 minutes at ambient temperature. The solution was poured into 150 ml of iced water and concentrated hydrochloric acid was added until a pH of 1. The precipitate was filtered, washed with water and then dissolved in tetrahydrofuran. The organic phase was dried, and concentrated to dryness under reduced pressure. The residue was taken up in ether, filtered and dried under reduced pressure at 80° to obtain 5.3 g of 2-[(1S) 1-(acetylamino)-propyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 275° C. and having a specific rotation of [α]D =+43.5°±4° (c=0.3% in DMF).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[C:27]([CH:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH:29]([C:27]#[N:28])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:31]=1)=[O:24]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: C=C=C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
2.06 g of dicyclohexylcarbodiimide were added at 0° C. to a solution of 1.52 g (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylic acid in 30 ml of methylene chloride followed by the addition of a few crystals of 4-dimethylamino-pyridine after which the mixture was stirred at 0° C. for 15 minutes. A solution of 2.47 g of (RS)α-cyano-3-phenoxy-benzyl alcohol in 10 ml of methylene chloride was added to the mixture which was stirred at 20° C. for 4 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 3-7 benzene-petroleum ether (b.p.=35° to 70° C.) mixture and then with a 7-3 benzene-petroleum ether (b.p.=35° to 70° C.) mixture yielded 2.89 g of (RS)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: NCc1ccccn1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCc1ccccn1

Procedure:
The product was made from D-glucose and 2-aminomethyl-pyridine comparable as in Example A. A resin-like, yellow product was obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:18][CH:16]1[CH2:15][N:14]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])[CH2:17]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (100 mg, 0.395 mmol) in DCM (5 ml) at 0° C. was added TEA (120 mg, 1.2 mmol) and methansulphonyl chloride (110 mg, 0.94 mmol). The mixture was stirred for 2 h at RT, then diluted with DCM (15 ml) and washed with saturated NaHCO3 (10 ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated providing the title compound as pale yellow solid (130 mg, 92%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:27](=[O:28])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 98.7 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (0.65 g, 3.23 mmol) was treated with (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (1 g, 3.23 mmol), N,N-diisopropylethylamine (1.9 mL, 10.66 mmol) and T3P® (50% in ethyl acetate, 2.7 mL, 4.52 mmol) according to the method of Preparation 5a to give 1.57 g (98% yield) of the desired compound. Purity 97%.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:10]([OH:22])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCCl>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@@H:10]([O:22][C:48]([C:43]2[C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
A mixture of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (16) (213 mg, 0.36 mmol), 4-dimethylaminopyridine (67 mg, 0.55 mmol) in dry 1,2-dichloroethane (10 mL) was stirred at room temperature. Biphenylcarbonyl chloride (119 mg, 0.55 mmol) was added to the stirred reaction mixture. The resulting suspension was stirred under reflux for 3 hours. The reaction mixture was cooled to 10° C. and filtered. The crystalline solid was washed on the funnel with dry 1,2-dichloroethane (5 mL) and filtered. The filtrates were combined, diluted with CHCl3 (20 mL) and washed twice with diluted brine solution (water-brine 2:1) (15 mL). The organic layer was dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—CHCl3 1:1 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-4-O-biphenylcarbonyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (17) (18mg, 65%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2].O1CCCC1>[Pd].C(O)C>[C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([OH:28])[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(O)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(O)(COc1ccc(N)cc1)O2

Procedure:
Following the same procedure as described in Preparation 24, 7 g of 6-acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 43) were treated with 5 g of 10% w/w palladium-on-carbon, 100 ml of tetrahydrofuran and 100 ml of ethanol, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1ccccc1N
Product: COc1cc(Br)ccc1N

Procedure:
2-Methoxyaniline was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one to give 4-bromo-2-methoxyaniline which was reacted with di-tert-butyldicarbonate in tetrahydrofuran to protect the amine group. The product was treated with butyllithium at -78° C. and then with trimethyltin chloride to give 4-tert-butoxycarbonylamino-3-methoxyphenyl trimethyl stannane.