Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]=[C:29]([C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)[NH2:30]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:30]=[C:29]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: NC(=NO)c1cnccn1
Product: CCc1ccc(C2CC(c3nc(-c4cnccn4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 46 mg (0.33 mmol, 1.5 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 24 mg (23% of theory)
Reaction SMILES: C(OP(CO[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]2[CH:34]([OH:35])[CH2:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:31]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([O:51][CH3:52])[CH:45]=3)[C:30](=[O:53])[N:29]2[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([OH:61])=[C:57]([O:62][CH3:63])[CH:56]=2)[CH:22]=1)(=O)OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:64]([O:71][P:72]([CH2:82][O:83]C1C=CC=CC=1CC1C(O)CN(CC2C=CC=CC=2)N(CC2C=CC(O)=C(OC)C=2)C(=O)N1CC1C=CC(O)=C(OC)C=1)(=[O:81])[O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>>[CH2:74]([O:73][P:72]([CH2:82][O:83][C:26]1[CH:21]=[CH:22][C:23]([CH2:27][CH:28]2[CH:34]([OH:35])[CH2:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:31]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([O:51][CH3:52])[CH:45]=3)[C:30](=[O:53])[N:29]2[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([OH:61])=[C:57]([O:62][CH3:63])[CH:56]=2)=[CH:24][CH:25]=1)(=[O:81])[O:71][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: COc1cc(CN2C(=O)N(Cc3ccc(O)c(OC)c3)N(Cc3ccccc3)CC(O)C2Cc2ccccc2OCP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1O
Reactant: COc1cc(CN2C(=O)N(Cc3ccc(O)c(OC)c3)N(Cc3ccccc3)CC(O)C2Cc2cccc(OCP(=O)(OCc3ccccc3)OCc3ccccc3)c2)ccc1O
Product: COc1cc(CN2C(=O)N(Cc3ccc(O)c(OC)c3)N(Cc3ccccc3)CC(O)C2Cc2ccc(OCP(=O)(OCc3ccccc3)OCc3ccccc3)cc2)ccc1O

Procedure:
The meta substituted analog {3-[1-Benzyl-6-hydroxy-2,4-bis-(4-hydroxy-3-methoxy-benzyl)-3-oxo-[1,2,4]triazepan-5-ylmethyl]-phenoxymethyl}-phosphonic acid dibenzyl ester or the ortho analog, {2-[1-Benzyl-6-hydroxy-2,4-bis-(4-hydroxy-3-methoxy-benzyl)-3-oxo-[1,2,4]triazepan-5-ylmethyl]-phenoxymethyl}-phosphonic acid dibenzyl ester, are prepared using the same methods except replacing the p-benzyloxyepoxide 13 with the meta- and ortho-substituted benzyloxy epoxides, 11 and 8, respectively.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[N:36]([CH3:45])[C:35]=2[CH:46]=1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:42]3[CH2:43][CH2:44][N:39]([C:37]4[N:36]([CH3:45])[C:35]5[CH:46]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=5[N:38]=4)[CH2:40][CH2:41]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1c(N2CCNCC2)nc2ccc(F)cc21
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccc(F)cc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 6-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCOC(=O)Cc1csc(N2CC[C@H](N)[C@H](OC)C2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)Cc1csc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)n1
Yield: 36 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-[2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazol-4-yl]acetate obtained in Example (64d) (about 0.29 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (45 mg, 0.26 mmol), WSC hydrochloride (150 mg, 0.78 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 42.6 mg of the title compound (36%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:22][C:14]1[CH:15]=[C:16]2[C:21]([N:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]2[C:13]=1[C:4]1[C:3]([S:8](=[O:10])(=[O:9])[NH:11]2)=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(c(F)cc3cccnc23)-c2ccccc21
Yield: 18.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(6-fluoro-quinolin-8-yl)-benzenesulfonamide (Intermediate 290) (200 mg, 0.63 mmol), t-butyl nitrite (0.11 ml, 0.94 mmol), AcOH (2 ml) and THF (2 ml) gave the title compound (35 mg, 19%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([O:10][C:11]2[CH:12]=[C:13]([CH3:27])[C:14]3[CH:18]([CH2:19][C:20]([O:22]CC)=[O:21])[O:17][B:16]([OH:25])[C:15]=3[CH:26]=2)[S:8][CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:20]([CH2:19][CH:18]1[O:17][B:16]([OH:25])[C:15]2[CH:26]=[C:11]([O:10][C:7]3[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=3)[CH:12]=[C:13]([CH3:27])[C:14]1=2)([OH:22])=[O:21]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nc(C(=O)OC)cs3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nc(C(=O)O)cs2)cc2c1C(CC(=O)O)OB2O
Yield: 7.4 %

Procedure:
A solution of 2-(3-ethoxycarbonylmethyl-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-thiazole-4-carboxylic acid methyl ester (500 mg, 1.28 mmol) in THF (30 mL) was treated with LiOH (107 mg, 2.55 mmol) in water (15 mL) at room temperature for 1 h. The reaction was concentrated to dryness. The residue was diluted with water and adjusted to pH 3. The mixture was purified by preparative HPLC to give the title compound (33 mg). 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 5.70-5.66 (m, 1H), 3.27-3.10 (m, 1H), 2.39 (s, 3H), 2.36-2.31 (m, 1H). MS found: (M+H)+: 350.1.
Reaction SMILES: [CH:1](OC)(OC)OC.[Cl:8][C:9]1[C:10]([NH:22][NH2:23])=[N:11][CH:12]=[C:13]([CH:21]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[Cl:8][C:9]1[C:10]2[N:11]([CH:1]=[N:23][N:22]=2)[CH:12]=[C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Reactant: COC(OC)OC
Product: CC(C)(C)OC(=O)c1cc(Cl)c2nncn2c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Trimethyl orthoformate (19 mL, 172 mmol) was added neat to tert-butyl 5-chloro-6-hydrazinonicotinate (1.9 g, 7.8 mmol). The mixture was heated to 85° C. After 4 h, the mixture was cooled to ambient temperature and concentrated to dryness: LC-MS [M+1]=254.1.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([NH:26][C:24]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:7]([CH2:6][S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[CH:25]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CS(=O)C(C)(C)C

Procedure:
Prepared according to the procedure described in Example 2 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (1 equivalent).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (923 mg, 2.99 mmol) and 2-methylpropane-2-sulfinamide (1.450 g, 11.96 mmol, 4 eq.) in anhydrous THF (75 mL) was added Ti(OEt)4 (5.46 g, 4.96 mL, 23.92 mmol, 8.0 eq). The resulting mixture was heated to reflux overnight. LC-MS showed ca. 45% conversion. After another 8 h, no further improvement. To the refluxing mixture was added 2-methylpropane-2-sulfinamide (0.725 g, 5.98 mmol, 2 eq.) and Ti(OEt)4 (2.73 g, 2.5 mL, 11.96 mmol, 4.0 eq) and followed by another equal portions of 2-methylpropane-2-sulfinamide and Ti(OEt)4 after 14 hours. The reaction mixture was refluxed for another 2 days, 93% conversion achieved at this point. The reaction was quenched with brine (3 mL) after cooled down to room temperature. The mixture was stirred for another 30 min before filtered through a short pad of Celite®. The filter cake was washed with EA, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography. The fraction of desired product with 2-methylpropane-2-sulfinamide was dissolved in EA (100 mL) and washed with saturated aqueous NaHCO3 (45 mL), 1 M NaOH (40 mL) and brine successively. Solvent was removed under reduced pressure after dried over Na2SO4 and filtered to afford 0.968 g of the desired product 4 as a light yellow solid. MS ESI+ve m/z 412 (M+H)30.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1>[CH3:13][N:14]1[C:2](=[O:3])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccccc2c1=O

Procedure:
6 g isatoic anhydride was stirred in 100 ml dry tetrahydrofurane (THF) and methylamine was passed through the mixture for 5 min. The resulting solution was evaporated and the residue was again dissolved in THF (100 ml) and charged with 15 ml 30% phosgene solution in toluene. The mixture was heated to reflux and additional 15 ml phosgene solution was added. After 4 hours reflux the mixture was cooled and evaporated to dryness. The residue was treated with water and the crystals were collected by filtration. The yield was 3.5 g. M.p. 240.4° -240.5° C. In the same manner, from the appropriate substituted isatoic anhydrides, the following compounds were synthesized:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[OH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1
Reactant: OCC1CCNCC1
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: OCC1CCN(c2ccncc2)CC1
Reaction time: 48 h
Yield: 70 %

Procedure:
The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol), 4-piperidinemethanol (1.82 g, 15.8 mmol), Cu(OAc)2 (2.88 g, 15.8 mmol), DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activated molecular sieve in 50 mL dry DCM was stirred for over 2 days. It was diluted with DCM, filtered through celite. It was washed with brine and water, dried, filtered through a silica plug, evaporated in vacuuo to give 4-(4-hydroxylmethylpiperidin-1-yl)pyridine in 70% yield. ES-MS: (M+H)+193.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: CC#N
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 83.2 %

Procedure:
A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (80 mg, 0.14 mmol) and morpholine (150 μL, 1.73 mmol) in acetonitrile (2.5 mL) was heated at 100° C. for 70 minutes in a microwave reactor. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a colourless glass (70 mg). LCMS (Method D, ESI): RT 4.94 min, m+H=601.0; 1H NMR (400 MHz, CDCl3): δ 8.63 (ddd, J=4.8, 1.7, 0.9 Hz, 1 H); 8.44 (d, J=2.5 Hz, 1 H); 7.84-7.85 (m, 2 H); 7.66 (dd, J=9.1, 2.5 Hz, 1 H); 7.44-7.45 (m, 3 H); 7.29 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49-6.50 (m, 2 H); 5.49 (dd, J=12.1, 2.1 Hz, 1 H); 4.28 (d, J=16.9 Hz, 1 H); 3.80 (t, J=4.8 Hz, 5 H); 3.63 (t, J=4.8 Hz, 4H); 2.83-2.85 (m, 2 H); 2.71 (d, J=12.1 Hz, 1 H); 2.47-2.50 (m, 2 H).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8](=[CH2:10])[CH3:9].Cl>O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C=C(C)C
Agent: Cl
Solvent: O
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Yield: 96.5 %

Procedure:
To 97.5 ml. (1 mole) of anhydrous chloral 0.5 g. of ferric chloride hexahydrate is added. To the obtained yellow clear solution 58-59 g. of isobutylene are introduced so that the temperature does not exceed 15°-20° C. To the reaction mixture a mixture of 35 ml. of water and 15 ml. of concentrated hydrochloric acid is added and the layers are separated. The organic layer is washed with water, diluted with benzene and water is removed from the mixture in a vacuo of 100 Hgmm. 194.6 g. (96.5%) of 1,1,1-trichloro-4-methyl-4-pentene-2-ol are obtained. Active ingredient content: 98.2%. The product can be further purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid (1 g, 4.35 mmol) was stirred in thionyl chloride (2 ml) at 37° for 72 h then the thionyl chloride was removed under reduced pressure. The residue was rotovapped from benzene (×3) affording the title compound as a yellow oil. (1.1 g, quant) 1H NMR(400 MHz, CDCl3) δ 7.46 (dd, J=8.3 Hz, 4.4 Hz, 2H), 7.23 (d, J=8.3, 1H), 2.00 (dd, J=4.6, Hz, 7.6 Hz, 2H), 1.485(dd, J=4.6, Hz, 7.6 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:8]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccccc1)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenoxy-2-(2-phenoxyacetamido)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated 3 under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 38 mg of 4-phenoxy-2-(2-phenoxyacetamido)benzoic acid as white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:18])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Br)ccc[n+]1[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromopicolinonitrile (1.0 eq.) in chloroform (0.3 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (1.8 eq.) and heated at 60° C. for 2 days. After cooling to room temperature, Ca(OH)2 (2.5 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 5% methanol in dichloromethane. The filtrate was washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted several times with 3% methanol in dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The crude product was stiffed in hot hexane/ethyl acetate (1:1), filtered, and dried to give the desired product as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C:15]1[CH:25]=[C:24]([C:26](OCC)=[O:27])[CH:23]=[CH:22][C:16]=1[C:17](OCC)=[O:18].S(=O)(=O)(O)O>C1COCC1>[OH:18][CH2:17][C:16]1[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:15]=1[C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[CH3:7]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(-c2cc(C)ccc2C)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(-c2cc(CO)ccc2CO)c1
Temperature: 67 °C
Reaction time: 2 h

Procedure:
LiAlH4 (7.9 g, 208 mmol) together with about 250 ml of THF were placed in a reaction vessel under a blanket of argon. Diethyl 2-(2′,5′-dimethylphenyl)terephthalate (48.6 g, 149 mmol) (cf. C3) was diluted in a dropping funnel with about 60 ml of THF and slowly added dropwise. The reaction mixture was stirred vigorously during this addition. The mixture was diluted with another 100 ml of THF and then refluxed at 67° C. After 2 hours, it was cooled to RT. While cooling on a water bath and blanketing with argon, ice water was added dropwise until gas evolution had ceased. Dilute (10% strength) sulfuric acid was subsequently added dropwise until the turbid gray mixture became clear. The phase mixture was separated by addition of a generous amount of chloroform and the aqueous phase was subsequently shaken twice with chloroform. The organic phases were shaken once with H2O and evaporated. The crude product was recrystallized from chloroform/hexane: 24.7 g (68%) of colorless, microcrystalline powder; melting point: 145-148° C. (purity>95%).
Reaction SMILES: C(OC([N:8]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[CH:46][N:45]=1)[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[N:37]=[CH:36][C:35]4[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=4)[C:29]3=[O:43])[C:18]=2[CH2:19][O:20]C(=O)C)[CH:10]=1)=O)(C)(C)C.O.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:17]([C:11]3[CH:10]=[C:9]([NH:8][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][N:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)=[CH:46][N:45]=4)[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=3)[C:18]=1[CH2:19][OH:20])[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)OCc1c(-c2cc(N(C(=O)OC(C)(C)C)c3ccc(CN4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Acetic acid 2-(5-{tert-butoxycarbonyl-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (1.5 g, 1.92 mmol) was dissolved in 19 ml of dioxane. Lithium hydroxide monohydrate (404 mg, 9.62 mmol) was dissolved in 19 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for 2 hrs. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (20 ml) and heated in a microwave reactor at 140 degrees for 30 min. The reaction was concentrated and the residue was purified by flash chromatography using a gradient of 0% to 15% methanol in DCM. The residue was diluted with DCM and concentrated again. Isopropyl acetate was added and the mixture was heated in a water bath to form a solution. The solution was cooled to room temperature and allowed to stand at room temperature overnight. The solid that formed was filtered and dried to give 185 mg of 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-phthalazin-1-one. A second crop of crystals yielded 88 mg of product for a combined yield of 273 mg (22.3%). MS: (M+H)+=638; MP=235.0-238.0° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.12 (s, 3 H) 2.19-2.41 (m, 8 H) 3.60 (s, 3 H) 4.32-4.40 (m, 2 H) 4.58-4.63 (m, 1 H) 4.60-4.61 (m, 1 H) 7.25 (d, J=8.59 Hz, 1 H) 7.34-7.44 (m, 3 H) 7.52 (s, 2 H) 7.52-7.54 (m, 1 H) 7.74 (dd, J=13.14, 1.52 Hz, 1 H) 7.87 (d, J=1.52 Hz, 1 H) 8.04 (d, J=2.02 Hz, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[C:4]=1[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].B(Br)(Br)Br>>[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:4]=1[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)CCC(=O)O
Agent: BrB(Br)Br
Product: O=C(O)CCC(=O)c1c(O)cccc1O

Procedure:
3-(2,6-Dimethoxybenzoyl)propionic acid was demethylated with boron tribromide according to the general procedure of Example 22(i) to give 3-(2,6-dihydroxybenzoyl)propionic acid.