Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Reactant: Cc1cc(O)ccc1Br
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Br

Procedure:
Mitsunobu coupling of 4-Bromo-3-methyl-phenol and 4-(4-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as described in a previous example gave 4-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:41]=[CH:40][CH:39]=[CH:38][C:31]=1[O:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][O:32][C:31]1[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: CC(C)(O)COc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(C)(C)O)cc1
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 700 mg, 1.674 mmol), 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.8 g, 11.722 mmol), Pd2(dba3)2 (96 mg, 0.1674 mmol), Xantphos (306 mg, 0.3349 mmol) and sodium-tert-butoxide (402 mg, 4.186 mmol) in toluene (15 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material, which was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to yield 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 88.2%). m/z (ESI) 582.1 (M+H)+.
Reaction SMILES: N1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1.N>>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=c1cccn[nH]1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2CCCC2=O)cc1

Procedure:
The title compound was prepared using the procedure described in Example 35B substituting pyrrolidin-2-one for pyridazin-3(2H)-one and substituting the product from Example 35A for the product from Example 34F. 1H NMR (300 MHz, CD3OD) δ 0.89-0.96 (m, 1H), 1.01-0.08 (m, 1H), 1.22 (d, J=6 Hz, 3H), 1.25-1.30 (m, 1H), 1.48-1.55 (m, 1H), 1.8-1.89 (m, 4H), 2.03-2.27 (m, 4H), 2.57 (t, J=6 Hz, 2H), 2.65-2.74 (m, 1H), 3.22 (q, J=6 Hz, 1H), 3.33-3.40 (m, 1H), 3.89 (t, J=6 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 299 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([C:29]#[CH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)[OH:8])(=O)C.O>CO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([C:29]#[CH:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([CH:7]([OH:8])[CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C#Cc1cnc(-c2ccc(C(O)CCOC(C)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CO
Solvent: O
Product: C#Cc1cnc(-c2ccc(C(O)CCO)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 3-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)-3-hydroxypropyl acetate C-243 (390 mg, 0.92 mmol, 1.0 equiv.) in MeOH (10 mL) was stirred at 23° C., 1 NNaOH was added until the PH of the solution reached 11˜12. After 1 hour, H2O (20 mL) and 1 NHCl were added until the PH of the solution reached 3-4. The reaction mixture was extracted with THF and washed with water, brine, dried and evaporated. The crude product was crystallized with THF/isopropyl to afford 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)propane-1,3-diol (Compound 242) (250 mg, 71.3%). LC-MS (m/z)=382.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (m, 2H), 0.98-1.00 (m, 2H), 1.84-1.88 (m, 2H), 1.93-1.98 (m, 1H), 3.47-3.59 (m, 2H), 4.53 (t, J=4.8 Hz, 1H), 4.84 (s, 1H), 4.92-4.96 (m, 1H), 5.72 (d, J=4.8 Hz, 1H), 6.54 (s, 1H), 7.02 (d, J=3.6 Hz, 1H), 7.72 (d, J=3.2 Hz, 1H), 8.45 (s, 1H), 8.55 (s, 1H), 12.27 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[C:34]([CH3:48])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:58])=[C:34]([CH3:48])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)c(C)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)c(C)c2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was suspended in dichloromethane (100 ml) and the suspension was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.35 g) in dichloromethane (5 ml) was added dropwise to the suspension. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 41) (0.54 g) as yellow amorphous.
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][CH:3]=[CH:2]2.[Br:9]Br.S([O-])([O-])=O.[Na+].[Na+]>O.CCCCCC>[Br:9][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][C:1]=2[CH:2]=1
Reactant: c1ccc2c(c1)CC2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc2c(c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bicyclo[4.2.0]octa-1(6),2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature. Upon cooling by an ice-water, 3.9 mL of bromine was added dropwise. Upon completion of the addition, the ice-water bath was removed and the reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of n-hexane and sodium sulfite (3 g, 23.8 mmol) was added. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. Then the separated organic layer was dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 3-bromo-bicyclo[4.2.0]octa-1(6),2,4-triene 5b (13.53 g) as a colourless oil, which was directly used in the next step.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:13]([CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: [H][H]
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2Cc2cnc[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2Cc2cnc[nH]2)cc1

Procedure:
The product from Step 1 (6.17 mmol) was dissolved in absolute ethanol followed by the introduction of 10% Pd/C catalyst then hydrogen under atmospheric pressure. The catalyst was removed via filtration through filter-aid and the product was isolated by removing the solvent under reduced pressure.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][C:40]([F:43])([F:42])[F:41])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][C:40]([F:43])([F:41])[F:42])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 65 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide, gave Compound 139, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide (170 mg, 65%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.50-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C27H23F4N5O5 found 574 (MH+).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:26][C:27]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:46])[NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:33](C(OC(C)(C)C)=O)[CH2:32]1>>[F:44][C:42]([F:43])([F:45])[CH2:41][NH:40][C:39](=[O:46])[O:38][CH2:37][C@@H:34]1[CH2:35][O:36][C@H:31]([CH2:30][CH2:29][C:28]2[C:54]([F:58])=[CH:55][CH:56]=[CH:57][C:27]=2[NH:26][C:5](=[O:6])[C@H:4]([C@H:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[NH2:1])[CH2:32][NH:33]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccnc2ccccc12
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccnc2ccccc12

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=688 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH-].[Na+:25]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]([O-:22])=[O:21].[Na+:25]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])C(Cc1ccccc1)N=Cc1ccc(Cl)cc1Cl

Procedure:
A solution of 18.5 grams of 2,4-dichlorobenzaldehyde in 50 milliliters of ethanol was added to a solution of 16.5 grams of phenylalanine in about 50 milliliters of alcoholic sodium hydroxide (prepared from 4 grams of sodium hydroxide in 50 milliliters of 1:1 water:ethanol) to obtain sodium 2-(2,4-dichlorobenzalamino)-3-phenylpropionate (Schiff base) and water by-product in the reaction mixture. The solvent was evaporated and the residue was redissolved in ethanol and evaporatively distilled to remove the water in rotary evaporator. The vessel was flushed four times with 100 milliliter portions of toluene to obtain the Schiff base in a solid mixture.
Reaction SMILES: C([N:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH3:14])[C:6]2[CH:15]=[N:16][C:17]([Cl:19])=[N:18][C:5]1=2)C=C.O>O1CCOCC1>[Cl:19][C:17]1[N:16]=[CH:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[C:9]([CH3:11])([CH3:12])[CH2:10][NH:4][C:5]=2[N:18]=1
Reactant: C=CCN1CC(C)(C)C(=O)N(C)c2cnc(Cl)nc21
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)C(C)(C)CNc2nc(Cl)ncc21

Procedure:
9-allyl-2-chloro-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.21 g, 4.34 mmol, prepared by method C) and dichloro(2,7-dimethyl-octa-2,6-diene-1,8-yl) ruthenium (IV) (0.26 g, 0.43 mmol, prepared following Tetrahedron Letters, 1965, 47, 4187) were suspended in dioxane (10 mL) and water (30 mL) in a pressure tube. The resultant suspension was stirred at 100° C. over two nights.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=2[F:29])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[N+:39]([O-])=O.Cl>CN(C)C=O>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=2[F:29])[C:12]([O:16][CH3:17])=[CH:13][C:14]=1[Cl:15]
Reactant: COc1cc(Cl)c(NC(=O)OC(C)(C)C)cc1OCc1c(OC)ccc(F)c1F
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(N(C(=O)OC(C)(C)C)c2ccncc2N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)-5-chloro-2-(2,3-difluoro-6-methoxy-benzyloxy)anisole (0.2 g) in N,N-dimethylformamide (2 mL) was added sodium hydride (55%, 21 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 4-chloro-3-nitropyridine (78 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL)—methanol (5 mL). To the solution were added nickel(II) bromide (5 mg) and sodium borohydride (53 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give 3-amino-4-{N-(tert-butoxycarbonyl)-N-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]amino}pyridine (53 mg). This material was dissolved in diglyme (1 mL), and the solution was stirred at 150° C. for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=10/1). The obtained product was dissolved in ethyl acetate. To the solution were added diethyl ether and n-hexane, and the precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give the title compound (6 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].Cl.[Br:13]Br>C(OCC)C.C(Cl)(Cl)Cl>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(=O)CBr)cc1
Reaction time: 4 h

Procedure:
20 mmol of 1-(4-ethylphenyl)ethan-1-one, 1 ml conc. HCl were mixed in 20 ml diethyl ether at 0° C. under nitrogen. To this solution a solution of 20 mmol Br2 in 20 ml chloroform was added drop wise and left for four hours and then concentrated in vacuo to obtain 2-bromo-1-(4-ethylphenyl)ethan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10][Br:21])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnc(OC)c(CBr)c1
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A solution containing 6-methoxy-5-methyl-nicotinic acid methyl ester (4.00 g, 22.1 mmol), NBS (5.11 g, 28.7 mmol), and AIBN (0.90 g, 5.5 mmol) in CCl4 (100 mL) is warmed to reflux. After 5 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (500 mL) and washed successively with aqueous Na2S2O3 (300 mL), water (100 mL), brine then dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 9:1) to provide 3.10 g (54%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ3.90 (s, 3H), 4.07 (s, 3H), 4.46 (s, 2H), 8.19 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H) ppm; MS (EI): m/z 259 (M+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([I:17])=[C:8]([C:12]([I:16])=[CH:13][C:14]=1[I:15])[C:9]([OH:11])=[O:10])=[O:4].[NH4+:18].[OH-]>>[NH2:18][CH2:2][C:3]([NH:5][C:6]1[C:7]([I:17])=[C:8]([C:12]([I:16])=[CH:13][C:14]=1[I:15])[C:9]([OH:11])=[O:10])=[O:4]
Reactant: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: [NH4+]
Agent: [OH-]
Product: NCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I
Reaction time: 35 h
Yield: 98.4 %

Procedure:
6.34 g of 3-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoic acid (prepared as described in Example 3) (10.72 mmol) are dissolved in 250 ml of 25% NH4OH and the solution is kept in autoclave for 35 hours at r.t. The mixture is evaporated to dryness and the residue is then dissolved in H2O, adjusting the pH to 7 and yielding a precipitate, which is filtered. 5.74 g of 3-[(2-aminoacetyl)amino]-2,4,6-triiodobenzoic acid (10.04 mmol) are obtained.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C3CCCCO3)[C:18]2=[O:31])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O.Cl.[H][H]>CO.[Pd]>[OH:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[C:18]1=[O:31]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCN(CCOC3CCCCO3)C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1N(CCO)CCN1C1CCNCC1

Procedure:
A solution of 59.7 g of 1-(1-carbobenzoxy-4-piperidyl)-3-[2(2-tetrahydropyranyloxy)-ethyl]-imidazolidin-2-one in 1,200 ml of absolute methanol is hydrogenated at room temperature and normal pressure with the addition of 1 mol equivalent of hydrochloric acid and 6 g of palladium-on-charcoal catalyst until 2 mol equivalents of hydrogen have been taken up. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The residue is freed from moisture which is still adhering, by treatment with toluene. The reaction product is chromatographed on 2 kg of basic aluminium oxide using a mixture of chloroform/methanol (85:15) as the eluant mixture. In this way, 3-(2-hydroxyethyl)-1-(4-piperidyl)-imidazolidin-2-one is obtained in the form of a viscous oil, which is further used without additional purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([OH:17])=O)[N:14]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:30]=[CH:31][C:32]([NH:35][C:15]([C:13]2[N:14]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:23])([F:22])[F:1])[O:11][C:12]=2[C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:33][CH:34]=1
Reactant: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H18F6N4O4 (m/e) 504. obsd 505 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])(=O)=O.CCOCC>C(O)(=O)C>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([Cl:15])[CH:5]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(CCN)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCCc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.1 mol of 2-(4-Methoxy-phenyl)-ethylamine was dissolved in 200 ml of acetic acid, followed by addition of 1.5 eq. of sulfuryl chloride at 0° to 5° C. The solution was stirred at room temperature for 1 hour. 250 ml of ether was added and the resulted solid was collected by filtration. The solid was heated in 48% aqueous HBr at 135° C. for 4 hours, cooled to 0° C., and the crystal was collected by filtration and washed with small amount of methanol then with ethyl acetate. LC-MS showed the product as HBr salt had the expected M+H+ of 186. 1H NMR (Varian 300 MHz, CD3OD shifts relative to the solvent peak at 3.3 ppm) δ 7.2 (d, 1H) 7.0 (m, 1H) 6.9 (d, 1H) 3.1 (m, 2H) 2.9 (m, 2H).