Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][C:6](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:5][C:4]([CH3:26])([CH3:25])[S:3]1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)O1>>[CH3:27][C:2]1([CH3:1])[CH2:7][C:6]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)=[CH:5][C:4]([CH3:25])([CH3:26])[S:3]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC(C)(C)S1
Product: CC1(C)C=C(c2ccc(N)cc2)CC(C)(C)S1

Procedure:
The title compound was prepared from 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid 2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in Example 21, step (a)) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine according to the procedure of Example 15, step (c). Mass spectrum (ESI, m/z): Calcd. for C15H21NS, 248.1 (M+H), found 248.2.
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([N:21]2[CH2:24][C@H:23]([NH2:25])[C:22]2=[O:26])=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(#N)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([N:21]2[CH2:24][C@H:23]([NH:25][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]2=[O:26])=[O:20])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)N2C[C@H](N)C2=O)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C[C@H](NC(=O)Cc3ccccc3)C2=O)cc1

Procedure:
(S)-1-[[[(4-Methylphenyl)sulfonyl]amino]-carbonyl]-2oxo-3-aminoazetidine, triethylammonium salt (626 mg, see example 2) was dissolved in dry acetonitrile (25 ml) and stirred under nitrogen in an ice bath. Triethylamine (0.57 ml) was added, followed by phenylacetyl chloride (0.324 ml). After 3 hours an equal volume of water was added, the pH was adjusted to 7.5, and the acetonitrile was removed in vacuo. The aqueous residue was extracted twice with ethyl acetate to remove neutral material. The aqueous layer was then acidified to pH 2.0 and extracted three times with ethyl acetate. The acidic extract was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 544 mg. This crude product, and an additional 481 mg of crude product from two other runs were combined and purified by chromatography on a column of SilicAR CC-4 (100 g), using dichloromethane and dichloromethane:methanol, 99:1 as eluants. The amorphous product was crystallized from acetonitrile to give 154 mg of crystalline material, melting point 170°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:26][C:27]([OH:29])=[O:28])[CH2:8][CH2:7]1>O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:26][C:27]([OH:29])=[O:28])[CH2:10][CH2:11][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:14][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]1
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=[Pt]=O
Product: COc1ccc(N)cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a nitrogen purged aqueous (50 ml) solution containing 50 mg of PtO2 was added 50 mg of 1-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid (prepared by the procedure of Example 23). After hydrogenating in a Parr bomb for one hour, the solution was filtered and the aqueous filtrate freeze-dried to give the aniline derivative as a tan solid (95 percent yield), MP>240° C. dec, and further characterized by:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:29]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:33]1[CH2:38][CH2:37][N:36]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:28])[NH:11][C:12]3[CH:13]=[CH:14][C:15]([S:18]([N:21]([CH2:22][CH2:23][OH:24])[CH2:25][CH2:26][OH:27])(=[O:19])=[O:20])=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N(CCO)CCO)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N(CCO)CCO)cc3)c2)CC1
Yield: 18 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N,N-bis(2-hydroxyethyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:25]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:28]4[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=4[N:26]=3)=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]>CCO.[Pd]>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([C:25]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:28]4[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=4[N:26]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of ethyl 3-[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl]-3-(1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-benzo[d]imidazol-2-yl)acrylate (100 mg) and 10% Pd—C (18.74 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (91 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc(Cl)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(Cl)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-chloro-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22].CO.[H-].[Na+]>CN(C=O)C>[OH:25][C:24]1[N:26]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][C:23]=1[C:21]#[N:22]
Reactant: Cc1ccc(/C(=C\N(C)C)C(=O)c2ccccc2)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C#N)c(O)nc2-c2ccccc2)cc1
Temperature: 95 °C

Procedure:
A solution of (E)-3-(dimethylamino)-1-phenyl-2-p-tolylprop-2-en-1-one (Compound 113, 500 mg, 1.9 mmol), cyanoacetamide (175 mg, 2.1 mmol) and MeOH (0.2 ml, 2.2 mmol) in DMF (4 ml) was cannulated into a suspension of NaH (119 mg, 4.7 mmol, 95% in mineral oil) in DMF (2 ml) at room temperature. After the addition was completed, the reaction was heated to 95° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, concentrated in vacuo. The solid residue was triturated with diethyl ether, filtered and dried under high vacuum to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH:5]1[NH:27][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH:20]2[NH:28][C:29]([CH:31]([CH:51]([CH:53]([OH:56])[CH2:54][OH:55])[CH3:52])[NH:32][C:33]([CH:35]3[N:39]([C:40]([CH:42]([CH2:46][C:47]([OH:49])=[O:48])[NH:43][C:44](=[O:45])[CH:13]([CH2:14][S:15]([C:17]4[NH:59][C:58]5[CH:60]=[C:61]([OH:64])[CH:62]=[CH:63][C:57]=5[C:18]=4[CH2:19]2)=[O:16])[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:41])[CH2:38][CH:37]([OH:50])[CH2:36]3)=[O:34])=[O:30])[CH3:4].C(OC([N-:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][NH-:79])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:1][CH2:2][CH:3]([CH:5]1[NH:27][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH:20]2[NH:28][C:29]([CH:31]([CH:51]([CH:53]([OH:56])[CH2:54][OH:55])[CH3:52])[NH:32][C:33]([CH:35]3[N:39]([C:40]([CH:42]([CH2:46][C:47]([OH:49])=[O:48])[NH:43][C:44](=[O:45])[CH:13]([CH2:14][S:15]([C:17]4[NH:59][C:58]5[CH:60]=[C:61]([OH:64])[CH:62]=[CH:63][C:57]=5[C:18]=4[CH2:19]2)=[O:16])[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:41])[CH2:38][CH:37]([OH:50])[CH2:36]3)=[O:34])=[O:30])[CH3:4].[NH-:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][NH-:79]
Reactant: CC(C)(C)OC(=O)[N-]CCCCCC[NH-]
Agent: CCC(C)C1NC(=O)CNC(=O)C2Cc3c([nH]c4cc(O)ccc34)S(=O)CC(NC(=O)CNC1=O)C(=O)NC(CC(=O)O)C(=O)N1CC(O)CC1C(=O)NC(C(C)C(O)CO)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: [NH-]CCCCCC[NH-]

Procedure:
4.54 mg (4.05 μmol) β-Amanitin-(t-butyloxy-carbonyl)-hexamethylenediamide (I) was stirred at room temperature in 250 μl trifluoroacetic acid. After 2 minutes the excess TFA was evaporated at 20° C. and the remaining solid coevaporated 2 times with 1 ml acetonitrile and methanol. The crude amine was dissolved in 1000 μl dmso and prified on a LaPrep-HPLC: column: Kromasil 100-C18, 10 μm, 250×20 mm, with methanol/water (0.05% TFA), flow: 26 ml/min, detection at λ295 nm. Solvent A: 95% water: 5% methanol 0.05% trifluoroacetic acid. Solvent B: 10% water: 90% methanol 0.05% trifluoroacetic acid. Gradient: 0-5 min 100% A; 5-20 25 min 0% A; 25-27 min 100% A; 27-35 min 100% A. The fractions with the same retention time were collected and the solvents evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[CH:14]=[N:15][C:16]4[NH:20][N:19]=[CH:18][C:17]=4[C:10]=3[N:9]3[N:21]=[CH:22][N:23]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([N:20]1[C:16]2[N:15]=[CH:14][C:11]3[C:12](=[O:13])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[N:9]([N:21]=[CH:22][N:23]=4)[C:10]=3[C:17]=2[CH:18]=[N:19]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1-c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1ncc2c1ncc1c(=O)n(-c3ccccc3)c3ncnn3c12

Procedure:
0.01 mol. of 4-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-4-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1cc(Cl)ccc1Cl
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1cc(Cl)ccc1Cl

Procedure:
A solution of methyl dimethoxyacetate (0.823 g, 6.08 mmol) and 2,5-dichlorobenzylamine (1.0 g, 5.7 mmol) was heated to 90° C. in a sealed tube for 48 h. The crude material was purified by column chromatography on silica gel [eluting with 40% EtOAc in hexanes] to afford the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ=3.41 (s, 6H), 4.53 (d, J=6.6 Hz, 2H), 4.75 (s, 1H), 7.19-7.23 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H). MS (ES+): m/z=278/280/282 [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[O:39][C:40](=O)[C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:43]([C:44]([O:46][CH3:47])=[O:45])[C:42]=1[CH2:53]Br>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:53][C:42]4[C:41](=[CH:50][C:49]([O:51][CH3:52])=[CH:48][C:43]=4[C:44]([O:46][CH3:47])=[O:45])[C:40]3=[O:39])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OC)cc(C(=O)OC)c1CBr
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(OC)cc2c1CN(CC1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1Cc1ccc(OC)cc1)C2=O
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (57.4 mg, 0.142 mmol) and diisopropyl ethylamine (49 μl, 0.28 mmol) in acetonitrile (20 ml) at room temperature was added 2-bromomethyl-5-methoxy-isophthalic acid dimethyl ester (3.00 g, 7.45 mmol). The solution was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethyl acetate (50 ml) and washed with water (2×20 ml), 1 N hydrochloric acid (20 ml), brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column using a mixture of ethyl acetate/hexane (1:1) as eluent, which afforded 62 mg (71%) of 2-amino-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.[H-].[Na+]>O1CCCC1>[CH2:1]([C:8]1[C:13]([O:14][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(I)nc1Cc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)nc1Cc1ccccc1

Procedure:
12 g of 2-benzyl-3-hydroxy-6-iodopyridine was dissolved in 50 ml of tetrahydrofuran and 3.8 ml of chloromethyl methyl ether was added thereto. While stirring in an ice bath, 2 g of 60% oily sodium hydride was portionwise added to the mixture. After the addition of sodium hydride, the refrigerant was removed and the mixture was stirred at room temperature for 2.5 hours. Thereafter, in an ice bath, ice water was portionwise added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give 13 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1occc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccoc1C(=O)O

Procedure:
A mixture of 3-methyl-2-furoic acid, methyl ester [20.0 g, 0.14 mole, 0.14 mole, Organic Synthesis 39, 49 (1959)] and 20% NaOH solution (46 mL) was refluxed under argon for 2 hours. The cooled mixture was acidified with concentrated HCl (28.5 mL). The resulting white precipitate was collected, washed with water and dried in vacuo to give the title acid (16.53 g, 94%) as a white crystalline solid, mp 132-134° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18]CCC)[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[CH:28]([CH3:31])[CH2:27][C:26]([CH:33](Br)Br)([OH:32])[CH2:25]1)C1C=CC=CC=1.[CH2:36]([Li])[CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:36]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:11][CH2:12][CH3:13])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[CH:28]([CH3:31])[CH2:27][CH2:33][C:26](=[O:32])[CH2:25]1)[C:37]1[CH:14]=[CH:9][CH:10]=[CH:39][CH:38]=1
Reactant: [Li]CCCC
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(O)(C(Br)Br)CC(C)C2C)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCC(C)C2C)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a -78° C. solution of 30.4 g (0.050 mole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-dibromomethyl-4,5-dimethylcyclohexanol in 150 ml of tetrahydrofuran is slowly added over a period of 2 hours 47.7 ml (0.105 mole) of n-butyllithium (2.2 M in hexane). The reaction solution is stirred 2 hours longer at -78° C. and 10 minutes at 0° C. and then quenched by pouring into 300 ml of ice cold 1 N hydrochloric acid. The quenched reaction is extracted with two 250 ml portions of ether, the combined extract washed with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with ether-pentane to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:17]=[C:16]([CH2:18][O:19][CH3:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Na+].O>[CH3:20][O:19][CH2:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:21])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(COC)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(C)C(=O)c1cc(COC)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Dissolve the crude 5-methoxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (3.9 mmol) in 5 N NaOH (2 mL) and water (10 mL). Stir at room temperature for 30 min. Dilute with water (20 mL). Wash with dichloromethane, and acidify the aqueous layer with 5 N HCl to about pH=2. Extract with dichloromethane and concentrate to give the title compound (0.96 g, 93%). MS (ES): m/z=266 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:27])[CH2:15][S:16][C:17]2[S:21][C:20]([C:22]([O:24]CC)=[O:23])=[CH:19][CH:18]=2)[CH2:7]1.[OH-].[Na+].Cl>C(O)C>[C:22]([C:20]1[S:21][C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:18][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1ccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CSc1ccc(C(=O)O)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The total amount of the resultant product of (237-3) was dissolved in ethanol (5 mL), a 1 mol/L aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (485 mg) as a white solid.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([P:20]([OH:23])(=[O:22])[OH:21])[CH:14]([OH:19])[P:15]([OH:18])(=[O:17])[OH:16])C1C=CC=CC=1.[Na].[Cl-].[NH4+]>N>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([P:20]([OH:23])(=[O:21])[OH:22])[CH:14]([OH:19])[P:15]([OH:17])(=[O:16])[OH:18]
Reactant: O=P(O)(O)C(O)C(c1nccn1Cc1ccccc1)P(=O)(O)O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: O=P(O)(O)C(O)C(c1ncc[nH]1)P(=O)(O)O

Procedure:
3.4 g (0.0094 mole) of 2-(1-benzylimidazol-2-yl)-1-hydroxyethanediphosphonic acid are dissolved in 40 ml of liquid ammonia and then 1 g of sodium is added gradually, with stirring, in small portions until the blue colour of the solution is maintained for some considerable time. Then 2.35 g of ammonium chloride are added in portions. The ammonia is then removed by evaporation, the residue is taken up in 20 ml of hot water, the solution is filtered and then 10 ml of concentrated hydrochloric acid are added to the filtrate. The precipitated crystals are isolated by filtration and recrystallised from aqueous methanol, to give 2-(imidazol-2-yl)-1-hydroxyethanediphosphonic acid of m.p. 235° C. (dec.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1>C(O)C.COCCOC.C(OCC)(=O)C.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>[O:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)=[CH:12][CH:11]=2)=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: Brc1ccc(-c2ncccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1cnc(-c2ccc(-c3ccoc3)cc2)nc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A suspension of 3-furanboronic acid (672 mg, 6 mmol) in 2M aq. Na3CO3 (10 mL, 20 mmol) and ethanol (8 mL) was added to a solution of 2-(4-bromo-phenyl)pyrimidine (1.30 g, 5.55 mmol, prepared as described in U.S. Pat. No. 5,780,473) and tetrakis(triphenylphosphine)palladium (693 mg, 0.60 mmol) in DME (30 mL). The reaction mixture was refluxed for 18 h, cooled to rt, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexanes/ethyl acetate) gave 793 mg (65%) of the title compound. MS 223 (M+H)+.