Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[C:49]([CH3:50])=[N:48][N:47]=[N:46]3)=[C:41]([C:51]([F:54])([F:53])[F:52])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[C:49]([CH3:50])=[N:48][N:47]=[N:46]2)=[C:41]([C:51]([F:54])([F:52])[F:53])[CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
A solution of triphenylphosphine (450 mg, 1.72 mmol) in methylene chloride (20 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (306 mg, 1.72 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of the (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid (326 mg, 0.86 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (257 mg, 2.57 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid thiazol-2-ylamide (52 mg, 13%) as an amorphous white solid: EI-HRMS m/e calcd for C21H21F3N6OS (M+) 462.1450, found 462.1451.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([F:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (142 mg, a white solid) from (−)-1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (197 mg, 0.72 mmol, Amine-12, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:22]3[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]([OH:31])=O)[NH:24][C:23]3=[O:32])[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:33]([O:35][CH2:36][CH2:37][O:38][NH2:39])=[CH2:34].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:22]3[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]([NH:39][O:38][CH2:37][CH2:36][O:35][CH:33]=[CH2:34])=[O:31])[NH:24][C:23]3=[O:32])[C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)O)C1=O
Reactant: C=COCCON
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)C[C@H]1NC(=O)N([C@H](c2ncc(-c3ccc(I)cc3)[nH]2)[C@@H](C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid; hydrochloride salt (114 mg, 0.21 mmol) (prepared as described in example 8), O-(2-vinyloxy-ethyl)-hydroxylamine (26 mg, 0.25 mmol) (prepared as described in WO 02/06213) and N,N-diisopropylethyl amine (0.11 mL, 0.63 mmol) in N,N-dimethylformamide (2 mL) was added O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluororophosphate (110 mg, 0.25 mmol). The reaction mixture was stirred for 1 hour at room temperature then diluted with ethyl acetate and the organic layer washed successively with saturated aqueous sodium carbonate then brine, dried over sodium sulfate, filtered, concentrated and the residue purified by chromatography over silica gel eluted with ethyl acetate to give 2-((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-N-(2-vinyloxy-ethoxy)-acetamide (81 mg, 61%) as a solid. LC-MS: calcd for C27H28IN5O5 [M+H+] 630. Found 630.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(C2CCC3(CC3)CC=2)O1.[OH-].[Li+]>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][C:24]2([CH2:28][CH2:27]2)[CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccccc2c(C2=CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CC1(C)OB(C2=CCC3(CC2)CC3)OC1(C)C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc2ccccc2c(C2=CCC3(CC2)CC3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
(S)-2-tert-butoxy-2-(3-methyl-1-(spiro[2.5]oct-5-en-6-yl)naphthalen-2-yl)acetic acid was prepared following the procedure for (S)-2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetic acid of Example 12 except using 4,4,5,5-tetramethyl-2-(spiro[2.5]oct-5-en-6-yl)-1,3,2-dioxaborolane instead of 2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and that in the final step the reaction was heated to 50° C. overnight followed by an addition of 10 equivalents of lithium hydroxide and heating to 60° C. for four hours and then at 45° C. overnight. 1H-NMR: 400 MHz, (CD3OD) δ: 7.90 (d, J=7.6 Hz, 1H), 7.71 (br d, J=7.2 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.40 (m, 2H), 5.88 (s, 1H), 5.70 (s, 1H), 2.73 (m, 1H), 2.78 (s, 3H), 2.31 (m, 2H), 2.09 (m, 1H), 1.73 (m, 1H), 1.59 (m, 1H), 1.24 (s, 9H), 0.49 (m, 4H). LCMS-ESI− (m/z): [M−H]−calcd for C25H29O3: 377.22. found: 377.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:29][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNC(c1ccccc1)c1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Yield: 49 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 2.94 g (16.0 mmol) of benzhydrylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 3 mL of DMF solution at 80° C. for 1 hour. Thereafter, the mixture was diluted with ethyl acetate, and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the condensed residue, and solids were collected by filtration, followed by drying, thereby giving 744 mg of the target 5-chloro-2-{[N-(diphenylmethyl)glycyl]amino}benzoic acid (yield: 49%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[Cl:25])=[N:10][O:11][C:12]=1[CH3:13])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:25][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=1[C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[O:11][N:10]=1
Reactant: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(-c2noc(C)c2C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(2-chloro-4-methoxycarbonylmethyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid tert-butyl ester 24 (1.0 g, 2.7 mmol) is dissolved in trifluoroacetic acid (20 mL) and stirred at room temperature for 4 hours. Then the solvent is evaporated and the remainder is dried on high vacuum to afford 3-(2-Chloro-4-methoxycarbonylmethyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid 25 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=10.36 (s, 1H), 7.42 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.27 (dd, J=8.4 Hz, J=0.6 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 2H), 2.78 (s, 3H). MS calculated for C14H13ClNO5 (M+H+) 310.0, found 310.3.
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:43])=[C:9]([F:42])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[C:21]([CH3:24])[C:20]([F:25])=[C:19]([NH:26]CC3C=CC(OC)=CC=3)[N:18]=1)[CH:14]=[C:13]([C:36]([O:38]CC)=[O:37])[C:12]2=[O:41]>O>[NH2:26][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:42])=[C:8]([F:43])[C:7]=3[Cl:6])[C:12](=[O:41])[C:13]([C:36]([OH:38])=[O:37])=[CH:14]2)[C:22]([F:23])=[C:21]([CH3:24])[C:20]=1[F:25]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)c(C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reaction time: 3 h

Procedure:
To a mixed solution of 2.5 ml of 4N hydrochloric acid and 2.5 ml of acetic acid was added all amount of the above described ethyl 8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours and allowed to cool and stand. To the residue was added 10 ml of distilled water, and the solution was concentrated under reduced pressure. The procedure of adding 10 ml of ethanol and concentrating the solution under reduced pressure was repeated three times, and 6 ml of chloroform was added to the residue, and the mixture was heated under reflux with stirring for 1 hour and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 128 mg of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:23])([CH3:22])[C:9]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](OCC)=[O:13])=[O:10])=[CH:4][CH:3]=1>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]([CH3:22])([CH3:23])[C:9](=[O:10])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]2[OH:13]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the crude diethyl 2-(2-(4-bromophenyl)-2-methylpropanoyl)malonate (4982 mg, 12932 μmol) in concentrated H2SO4 (30 mL) was stirred at 23° C. After 2 hours, the reaction was poured into an ice-water mixture (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo affording ethyl 6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate as the product.
Reaction SMILES: Br[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[Na].[O:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[NH:13]1.O>CN(C)C=O>[O:21]=[S:14]1(=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12](=[O:11])[N:13]1[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: CC1(Br)CCCNC1=O
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(N2C(=O)c3ccccc3S2(=O)=O)CCCNC1=O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
6.8 g of 3-bromo-3-methyl-2-piperidone and 8 g of the dried sodium salt of 2,3-dihydro-3-oxo-1,2-benzisothiazol-1,1-dioxide are heated while stirring to 110°-115° in 25 ml of distilled dimethyl formamide for a period of 75 minutes. After cooling 75 ml of water are added and the stirring is continued for further 30 minutes. The precipitate is filtered off, washed with water, dried in a vacuum at 80° C. and then recrystallized from n-butanol. 3-(2,3-Dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-3-methyl-2-oxo-piperidine melting at 211° to 215° C. is thus obtained in a yield of 24% of the theoretical.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=O.Cl.[NH2:25]/[C:26](/[NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[N:27]/[H].[O-]CC.[Na+]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:27]=[C:26]([NH:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)[N:25]=2)[CH:13]=[CH:12][S:11]3)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(-c2nc3sccn3c2C(=O)C=CN(C)C)c1
Reactant: [H]/N=C(/N)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)c1
Yield: 92.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (5.0 g, 15.3 mmol) and tert-butyl (3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (5.28 g, 18.95 mmol) is diluted with 60 ml of absolute ethanol and treated with 1.15 eq. of a 21% w/w solution of sodium ethoxide in ethanol (6.56 ml) to form a reaction mixture. The reaction mixture is heated to reflux for 24 hours. Volatiles are removed in vacuo and the residue is taken up in 250 ml of ethyl acetate and 250 ml of water. The phases are separated and the aqueous phase is extracted with 250 ml of ethyl acetate. The combined organic extracts are washed with 250 ml each of water, and then with a saturated sodium chloride solution (250 ml). The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo, to give a yellow oil. The product is purified by flash chromatography on silica gel (ethyl acetate/hexanes, 50%) to yield 7.2 g of a pale yellow solid (93%). 300 MHz 1H NMR (DMSO-d6 at 80° C.) δ: 8.69 (d, J=3.5 Hz, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.32-7.41 (m, 2H), 7.12-7.18 (m, 2H), 6.91-7.02 (m, 2H) 6.41 (d, J=5.3 Hz, 1H), 3.94 (br. d, J=7.0, 1H), 3.74-3.88 (m, 1H), 3.78 (s, 3H), 3.67 (br. d, J=13.2, 1H), 2.86-3.02 (m, 2H), 1.90-2.06 (m, 1H), 1.70-1.84 (m, 1H), 1.38-1.64 (m, 2H), 1.34 (s, 9H). LCMS: 507 [M+H].
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11]([Cl:16])[N:10]=2)N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=O.Cl>O>[Cl:16][C:11]1[N:10]=[C:9]([N:7]2[C:1]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([CH2:21][C:22]([OH:24])=[O:23])=[C:18]2[CH3:17])[CH:14]=[C:13]([Cl:15])[N:12]=1
Reactant: NN(c1ccccc1)c1cc(Cl)nc(Cl)n1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Product: Cc1c(CC(=O)O)c2ccccc2n1-c1cc(Cl)nc(Cl)n1

Procedure:
A mixture of N-phenyl-N-(2,6-dichloropyrimidin-4-yl)hydrazine (30g.) and laevulinic acid (50g.) was heated at 100° C. for 3 hours whilst a stream of hydrogen chloride gas was passed through it. The mixture was cooled and added to water (400ml.), and the resulting mixture filtered to give 1-(2,6-dichloropyrimidin-4-yl)-2-methylindol-3-ylacetic acid, m.p. 205°-207° C.
Reaction SMILES: [C:1](=[O:20])([O:5][CH2:6][O:7][C:8](=[O:19])[CH2:9][CH2:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])SCC.S(Cl)([Cl:24])(=O)=O>>[CH2:14]([O:13][P:11]([CH2:10][CH2:9][C:8]([O:7][CH2:6][O:5][C:1]([Cl:24])=[O:20])=[O:19])([O:16][CH2:17][CH3:18])=[O:12])[CH3:15]
Reactant: CCOP(=O)(CCC(=O)OCOC(=O)SCC)OCC
Reactant: O=S(=O)(Cl)Cl
Product: CCOP(=O)(CCC(=O)OCOC(=O)Cl)OCC
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of carbonothioate 80 (1.29 g, 3.93 mmol) in ice-cold CH2Cl2 (20 mL) was added sulfuryl chloride (478 μL, 5.89 mmol) and the mixture was stirred at 0° C. for 2 h 35 min, after which the mixture was concentrated to dryness, providing chloroformate 81 as a colorless gum (1.44 g, >quant.) which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.1 Hz, 6H), 2.05-2.14 (m, 2H), 2.68-2.75 (m, 2H), 4.07-4.15 (m, 4H), 5.84 (s, 2H): 31P NMR (162 MHz, CDCl3) δ 30.08 (s).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Na+].[Na+].ClC(Cl)(Cl)[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1.Cl.[CH3:21]O>>[CH3:21][O:4][C:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[O:2]
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Na2CO3 (0.64 g, 6.07 mmol) was added to a solution of (17) (1.9 g, 6.07 mmol) in 20 mL MeOH. The reaction mixture was heated to reflux for 14 h and then cooled to RT. 1N HCl was added to the solution and the reaction mixture was stirred for 0.5 hour. The mixture was extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and evaporated to give the title compound (0.89 g, yield 83%). ESI-MS (M+1): 177 calc. for C9H8N2O2 176.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][OH:34])([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[C:18]([Cl:35])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH2:43](Cl)[O:44][CH3:45].O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:43][O:44][CH3:45])([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[C:18]([Cl:35])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC(CO)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OC
Reactant: COCCl
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)OC

Procedure:
The compound of Example 212 (1.12 g) was dissolved in acetonitrile (30 mL). To this solution, diisopropylamine (0.58 mL) and MOMCl (0.25 mL) were added while the solution was stirred and chilled in an ice bath. The mixture was stirred overnight. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous magnesium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired product as a colorless oil (1.12 g).
Reaction SMILES: Br[C:2]1[C:3]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC.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>[CH3:29][N:28]([CH3:30])[C:26]([C:3]1[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[O:27]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 125 °C

Procedure:
Phenylmethyl 5-bromo-4-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 39; 195 mg) was redissolved in 1,2-dimethoxyethane (5 ml) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 0.49 mmol), tripotassium phosphate (168 mg, 0.79 mmol) and Pd(Ph3P)4 (34.3 mg, 0.03 mmol) were added. The mixture was heated at 125° C. for 50 minutes. Ethyl acetate (10 ml) and water (10 ml) were added. The organic layer was separated and dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 1:1 ethyl acetate/cyclohexane-10% 2M NH3 in CH3OH/dichloromethane) gave the title compound as a brown gum. 195 mg.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1)#[N:2].C([Sn]([N:62]=[N+:63]=[N-:64])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][CH2:9][O:8][C:7]2[CH:45]=[CH:46][CH:47]=[CH:48][C:6]=2[CH2:5][CH2:4][CH2:3][C:1]2[NH:64][N:63]=[N:62][N:2]=2)=[CH:19][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCC#N)cc1
Solvent: Cc1ccccc1C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCc2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.40 g of tert-butyl 3-{2-[2-(3-cyanopropyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 55a) and 0.34 ml of tributyltin azide in 8 ml of o-xylene is stirred at 145° C. over 19 hours. The reaction mixture is concentrated by evaporation, the residue is taken up in 12.5 ml of 40:10:1 dichloromethane-methanol-25% conc. ammonia and stirred at room temperature over 1 hour. The mixture is concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.65 (40:10:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.61.