Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]1[C:34]([CH3:35])=[C:33](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:45])=[N:31]1.C(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.C1(C)C=CC=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:33]3[C:32]([CH3:45])=[N:31][N:30]([CH3:29])[C:34]=3[CH3:35])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3c(C)nn(C)c3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 29 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg, 0.325 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 18 h then cooled to room temperature and partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 50% AcOEt in Hexanes) gave 1-methylethyl[(cis)-1-acetyl-2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (33 mg, 0.078 mmol, 29%) as a dark yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)=O)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>B(F)(F)F.CCOCC>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CS(=O)c1nccc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: Nc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
A mixture of 4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (0.5 g, 1.58 mmol) and aniline (1.5 g, 15.8 mmol) is heated at +100° C. After the addition of boron trifluoride diethyl etherate (3 drops) the solution is heated at +150° C. for half an hour. On cooling the product starts to crystallize. The crystals are filtered and washed thoroughly with diethyl ether to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine in pure form, having a m.p. of 244–245° C.
Reaction SMILES: [C:1]([C:3](=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[C:1]([C:3](=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4]([Cl:25])=[O:5])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: N#CC(C(=O)Cl)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a suspension of 2-cyano-3,3-bis(4-fluorophenyl)-2-propenoic acid (4 g, 14 mmol) in 10 mL of dry methylene chloride at room temperature was added oxalyl chloride (6 mL, 69 mmol) in one single portion. The reaction was stirred and warmed slowly to reflux for 45 minutes. The pale homogeneous solution was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride was removed under vacuum (20 mm Hg) at ambient temperature for 2 hours and under high vacuum (0.1 mm Hg) for 16 hours to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]([NH:16][C:17]([C@H:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH:21]([CH3:24])[CH2:22][CH2:23][C@@H:19]1[C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:18])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)NC(=O)[C@H]1CCC(C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CCC(C)N1c1nncc2cc(Br)ccc12
Temperature: 200 °C

Procedure:
6-Bromo-1-chlorophthalazine (215 mg, 881 μmol), (R)-N-isopropyl-5-methylpyrrolidine-2-carboxamide (150 mg, 881 μmol), and cesium carbonate (1435 mg, 4405 μmol) were added to acetonitrile (4.4 mL) and heated in the microwave oven for 80 min at 200° C. The reaction was diluted with 75 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give crude. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 377(M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37]([NH-:40])(=[O:39])=[O:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(O)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29]([NH:40][S:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH-]S(=O)(=O)c1cccs1
Reactant: O=C(O)/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To (E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoic acid (210 mg, 0.52 mmol) of Example 2 (step 2), 2-thiophenesulfonylamide (121 mg, 0.74 mmol) and DMAP (250 mg, 2.04 mmol) in CH2Cl2 (3 mL) was added EDCI (142 mg, 0.74 mmol). After stirring at r.t. for 2 days, the reaction mixture was poured into 1N HCl (or aqueous AcOH) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Tol:EtOAc:AcOH, 1:0:0 to 20:1:0.1) and recrystallization (Hex:CH2Cl2) provided the desired material as a white solid (161 mg, 56%). 1H NMR (acetone-d6) δ 5.13 (2H, s), 6.72 (1H, d), 7.04 (1H, td), 7.1-7.2 (2H, m), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.55 (1H, t), 7.62 (1H, dt), 7.7-7.8 (3H, m) and 7.92 (1H, dd).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH2:10])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH2:12]([N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[CH2:12]([N:19]1[CH2:23][CH2:24][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: c1ccc(CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
A mixture of 500 mg (3.78 mmole) 1H-indol-4-yl-amine, 993 mg (3.78 mmole) N-benzyl-bis(2-chloroethyl)amine hydrochloride, and 1.32 mL (7.6 mmole) diisopropylethylamine in 10 mL chlorobenzene was heated at 130° C. for 24 hours. Another 0.66 mL (3.8 mmole) diisopropylethylamine was added and the mixture was heated at 130° C. for an additional 5 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was extracted with 10 mL 3 N hydrochloric acid. The aqueous phase was washed with 15 mL ethyl ether, then made basic with 50% sodium hydroxide. The product was extracted with 25 mL dichloromethane, the organic phase was washed with 10 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. 4-(4-benzyl-piperazin-1-yl)-1H-indole (274 mg) was isolated as the hydrochloride salt from ethyl ether.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH2:20][CH2:19][C:18]=3[CH:22]=2)=[O:13])[CH2:8][CH2:7]1)C.O[Li].O>>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:11][CH2:10]3)=[O:13])=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Agent: [Li]O
Solvent: O
Product: O=C(O)CN1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of [4-(2,3-dihydro-benzofuran-5-carbonyl)-piperidin-1-yl]-acetic acid ethyl ester (0.18 g, 0.57 mmol in 6 mL of THF and 2 mL of methanol) was added LiOH.H2O (0.12 g, 2.8 mmol in 3 mL of water) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. and lyophilized for 24 hours to yield the title compound (0.16 g, 0.53 mmol). MS (ESI) m/z 289.7 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.23 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: NC1CCCCC1
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(NC3CCCCC3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and cyclohexylamine in DME. ES-MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.C(OCC)(=O)C.[CH3:18][N:19]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:18]#[N:19])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc2[nH]ccc2c1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-5 (90 mg, 0.46 mmol), zinc cyanide (80 mg, 0.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (53 mg, 46 μmol) were dissolved in N-methyl-2-pyrrolidinone (2 mL), and the mixture was stirred for 4.5 hours at 110° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (48 mg, 0.34 mmol, 73%) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])(OCC)=O)C.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[N:30]1>C1COCC1.CCOC(C)=O>[NH:29]1[CH:33]=[C:32](/[CH:34]=[CH:11]/[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:13])[CH:31]=[N:30]1
Reactant: O=Cc1cn[nH]c1
Reactant: CCOP(=O)(CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A 60% suspension of NaH in paraffin oil (192 mg, 5 mmol) was added portionwise to a solution of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate (1.93 g, 5 mmol) in anhydrous THF (25 mL) at 0° C. The reaction mixture was stirred for 30 min before being warmed up to room temperature. 1H-pyrazole-4-carbaldehyde (400 mg, 4.16 mmol) dissolved in anhydrous THF (5 mL) was then added and the reaction mixture was stirred for 72 h under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was diluted with EtOAc (80 mL) and quenched with a saturated NH4Cl solution (10 mL). The organic layer was separated and washed with water (40 mL) and brine (20 mL). It was dried over anhydrous Na2SO4 and the solid was filtered. The filtrate was evaporated under vacuum. The isolated crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexanes to provide 986 mg of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. 1HNMR (300 MHz, CD3OD): δ 7.93 (broad s, 2H), 7.64 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.2 Hz), 7.45 d, 1H, J=7.8 Hz), 7.11-7.24 (m, 2H), 6.59 (d, 1H, J=15.6 Hz), 1.50 (s, 9H), MS: ES+(M+Na)+: 351
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:2].C(NC(C)C)(C)C.[Li].[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:5]1[S:6][CH:7]=[CH:8][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: O=CNc1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sccc1NC=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3- Formylaminothiophene (Bull. Soc. Chim. Fr. 1976,151) (2 g), dissolved in dry THF (20 ml), was dropped into a freshly prepared solution of lithium diisopropylamine (0.035 mol) in THF (35 ml) at −70° C. The solution was warmed to −20° C. and stirred for 30 minutes, then cooled again to −70° C., whereupon trimethylsilylchloride (5 ml) was added. After stirring for an additional hour at this temperature the mixture was slowly warmed to room temperature and stirred for 4 hours. Quenching with a saturated solution of ammonium chloride, extracting with ethyl acetate, drying over sodium sulfate, removing the solvent and applying chromatography on silica gel (hexane:ethyl acetate 2:1) yielded 2-trimethylsilyl-3-formylaminothiophene (1.2 g) (m.p. 74-76° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:6][CH:5]=1
Reactant: C=CCO
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(CCC=O)cc1

Procedure:
A process disclosed in U.S. patent application Ser. No. 10/302,636 for making 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid may be summarized as follows: methyl-4-iodobenzoate is reacted with allyl alcohol to provide 4-(3-Oxo-propyl)-benzoic acid methyl ester, which is then reacted with 5-chloro-2-methylindole to yield 4-[3-(5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester; this product is reacted with benzhydryl bromide to produce 4-[3-(1-benzhydryl-5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester, which is then reacted with benzoyl peroxide to produce the 2-formyl indole; the 2 formyl indole is then reacted with nitromethane followed by Zn(Hg)/HCl to form the 2-(2-aminoethyl) indole; this amine is then reacted with [(3,4-dichlorophenyl)-methyl]sulfonyl chloride to produce 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid methyl ester, which is then hydrolyzed to form 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid. In this process, chromatography is used to separate some of the compounds made in the aforesaid reactions. It would be desirable to have a process for making the product that does not require the use of chromatography.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3]1.O[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:30]=[CH:31][C:24]=2[S:23]1(=[O:36])=[O:35]>CC(OCC)=O>[O:35]=[S:23]1(=[O:36])[C:24]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][C:25]=2[C:26](=[O:27])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[O:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: CC(C)c1ccc2c(c1)C(=O)N(CCCCO)S2(=O)=O
Reactant: O=c1oc2ccccc2n1C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(c1)C(=O)N(CCCCN1CCC(n3c(=O)oc4ccccc43)CC1)S2(=O)=O

Procedure:
From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)-1,1-dioxido-5-(2-propyl)-1,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: 1H NMR (400 MHz, CDCl3) 7.9 (s, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 7.3 (m, 1H), 7.2-7.0 (br m, 3H), 4.2 (m, 1H), 3.8 (m, 2H), 3.1 (m, 3H), 2.7-2.5 (br m, 2H), 2.1 (m, 2H), 2.0-1.8 (br m, 4H), 1.7-1.6 (m, 4H), 1.35 (d, 6H) Analysis calculated for C25H30 N3O6S·HCl·1.6 CH3CO2CH2CH3 C: 57.64, H: 6.69, N: 6.23 found C: 57.06, H: 6.12, N: 6.56.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[N:2]1
Reactant: Nc1nc[nH]n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1nc[nH]n1
Temperature: 110 °C
Yield: 25 %

Procedure:
To a mixture of 1H-1,2,4-triazol-3-amine (500 mg, 5.95 mmol) and TEA (0.829 mL, 5.95 mmol) in toluene (25 mL) was added pivaloyl chloride (0.732 mL, 5.95 mmol). The mixture was heated up at 110° C. for 13 h. The reaction mixture was quenched with water, filtered and the extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(1H-1,2,4-triazol-3-yl)pivalamide (250 mg, 25%) as white solid. 1H NMR (500 MHz, MeOD) δ ppm 1.48 (s, 9H) 7.48 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C(N(CC)CC)C.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:16][CH:17]2[CH2:18][CH2:19][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]2)[CH:2]=1
Reactant: COC(=O)C1CCC(N)CC1
Reactant: O=Cc1cccnc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1CCC(NCc2cccnc2)CC1
Temperature: 50 °C
Reaction time: 6.5 h

Procedure:
6.13 g of pyridine-3-aldehyde, 5.77 g of triethylamine and 9 g of methyl 4-amino-cyclohexanecarboxylate are mixed into 250 ml of methanol. 3 g of Raney nickel are added thereto un order to hydrogenate the mixture, with stirring, for about 6.5 hours at 50° C. and 3 bar. After the catalyst has been eliminated by suction filtering the filtrate is evaporated down. The crude product is purified through silica gel with methylene chloride/methanol.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH3:63]>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:62]([CH3:63])[CH3:61])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol) and dimethylamine (0.09 mL, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (9:1, methylene chloride/methanol) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (8.0 mg, 13%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.16 (s, 1H), 6.85 (d, J=9.0 Hz, 0.8H), 6.57 (s, 1H), 6.28-6.24 (m, 0.2H), 6.20 (s, 0.2H), 5.87 (s, 0.8H), 5.14-5.08 (m, 1H), 5.00-4.94 (m, 1H), 4.71-4.66 (m, 1H), 4.62-4.56 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m. 2H), 3.61 (s, 3H), 3.59-3.52 (m, 3H), 3.41 (s, 3H), 3.38-3.28 (m, 2H), 3.13 (t, J=9.0 Hz, 1H), 2.92 (s, 6H), 2.14 (s, 3H), 3.14 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 709 (M−H); HPLC 95.6% (AUC), tR 11.51 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])=[N:10]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2C)c2cccc(C(F)(F)F)c21
Yield: 53 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.090 g) as a white solid.