Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:6]2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CC(C)C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(CC(C)C)cc2c1
Yield: 100.1 %

Procedure:
Ethyl ester (107) (0.82 g, 1.70 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.77 g (˜100%) of the title compound (108) as an off-white foam. 1H NMR (400 MHz, CDCl3): δ 0.75 (d, J=6.4 Hz, 6H), 1.60-1.70 (m, 1H), 2.46 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=9.2 Hz, J2=2.2 Hz, 1H), 7.06-7.14 (m, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.18-7.25 (m, 5H), 7.54 (s, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 453 (M+H)+, m/z 451 (M−H)−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:9]CC.[CH2:12]([CH:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25](O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].OS(O)(=O)=O>O>[CH2:12]([CH:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][O:20][CH2:21][CH2:22][O:23][CH:24]([OH:9])[CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOCC
Reactant: CCCCCCCCC(CCCCCC)COCCOCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CCCCCCCCC(CCCCCC)COCCOC(C)O

Procedure:
In three-necked, one-liter, round-bottom flask (equipped with a reflux condenser, nitrogen inlet, dropping funnel, and magnetic stirring bar) 0.15 mole of lithium aluminum hydride was dispersed in 300 ml. of ether at room temperature and under a dry nitrogen atmosphere. The 2-hexyldecyloxyethoxyacetic acid from Part A was mixed with 200 ml. of ether and added dropwise with stirring. The resulting mixture was stirred overnight at room temperature. The flask containing the mixture was then cooled in ice, and icecold water was added dropwise to the mixture to react with any excess reducing agents. The reaction mixture was acidified with 10% H2SO4 to a pH of one, and extracted with 300 ml. of ether twice. The ether layers from the two extractions were diluted with an equal volume of water, and washed two times with saturated NaHCO3 solution. The mixture was then washed with water and dried with anhydrous magnesium sulfate. 2-hexyldecyloxyethoxyethanol was obtained after removing the ether.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[S:20][CH2:19][CH2:18][CH2:17][S:16]2)=[CH:13][S:12][C:11]=1[N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])=[O:9])C.Cl>O>[Cl:27][C:23]1[CH:22]=[C:21]([C:15]2([C:14]3[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])[S:12][CH:13]=3)[S:20][CH2:19][CH2:18][CH2:17][S:16]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(3-Chlorophenyl)-1,3-dithian-2-yl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 27 & 28, Part D). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][OH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][O:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: OCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and 2-phenyl-ethanol.
Reaction SMILES: Br[C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:4]2[CH:3]=1.O(C([N:34]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.O.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>[CH3:25][C:7]1[N:6]=[C:5]2[S:26][C:2]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[CH:3][C:4]2=[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
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: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-bromo-6-methyl-4-[(phenylsulfonyl)amino]thieno[2,3-b]pyridine-5-carboxylate (Description 67) (6.27 g, 13.77 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (8.10 g, 27.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.796 g, 0.688 mmol) and potassium carbonate (5.71 g, 41.3 mmol) in 1,4-dioxane (40 mL), DMF (20 mL) and water (10 mL) was heated at 100° C. for ca. 3.5 h. After cooling to RT, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified via normal phase chromatography eluting with 0-100% ethyl acetate in DCM, to give the title compound (5.81 g). LCMS (A) m/z: 443 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C

Procedure:
2-(4-Cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4) was dissolved in DCM. To this solution was added DMF and cooled to 0° C., followed by the addition of oxalyl chloride under stirring. To this mixture, a solution of 2-aminothiazole and pyridine in DCM was added drop wise at 0° C. and was stirred further for 4 h. at room temperature. The reaction mixture was poured into IN aqueous HCl under stirring, organic layer was again washed with 1N HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25]C)[C:15]2[C:20]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CC(C)Cc1cccnc1N(C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-[N-methyl-N-(3-(2-methyl-1-propenyl)-2-pyridinyl)amino]piperidine (XXII, EXAMPLE 16, 0.27 g, 0.80 mmol), Pearlman's catalyst (0.1 g), CDI (0.26 g, 1.6 mmol) and pyrrole-2-carboxylic acid (0.18 g, 1.6 mmol), the title compound is obtained, HRMS Calcd. for C20H28N4O=340.2263, found=340.2277.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Br)=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1c(CBr)cccc1Oc1ccccc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1F
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Powdered sodium cyanide (2.5 g) was added to a solution of 2-fluorophenyl 2-methoxy-3-bromomethylphenyl ether (17.6 g) in dimethyl sulfoxide (50 ml) with stirring at room temperature, and the reaction mixture was treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (10.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](O)([OH:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: OC1(O)CCNCC1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 2-methylbenzoyl chloride (800 mg, 5.2 mmol) in 5 mL of DICHLOROMETHANE was added a mixture of piperidine-4,4-diol hydrochloride salt 800 mg, 5.2 mmol) and potassium carbonate (716 mg, 5.2 mmol) in 5 mL H2O and stirred at room temperature for 2 hours. Layers were separated and aqueous layer was extracted with dichloromethane (3×10 mL). Organic layers were combined, dried, filtered and the filtrate was concentrated in vacuo to give the tile compound (1.2 g) as light yellow oil. MS (M+1): 218.0
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH3:28])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:31][N:32]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33](=[O:36])[CH2:34]Br>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:34][C:33]([N:32]([CH3:31])[CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C:12]3[C:17]([C:9]=2[C:8]=1[CH3:28])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: CN(CCc1ccccc1)C(=O)CBr
Reactant: Cc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A solution of 1.096 g of 5-benzyloxy-4-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (2.93 mmol) in 2.9 ml of tetrahydrofuran is added to a suspension of 92.2 mg of sodium hydride (3.03 mmol; 80% in mineral oil) at 0° C. under nitrogen, and it is stirred for 10 minutes at 0° C. Then, 750 mg (2.93 mmol) of N-methyl-N-phenylethyl-2-bromoacetamide is added, and it is then stirred for 18 hours at 24° C. It is filtered off on Celite, the filtrate is concentrated by evaporation in a vacuum, and the crude product that is thus obtained is purified on a silica gel column with hexane/0-100% ethyl acetate. In this way, 1.24 g of 5-benzyloxy-4-methyl-9-(2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as an amorphous, yellowish-colored solid with a melting point of 69°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and N-methyl-piperazine (35.3 mg, 0.35 mmol). The title compound was obtained as a solid (30.0 mg, 21% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (1H, m), 8.99 (2H, m), 8.51 (1H, s), 4.07 (2H, m), 3.42 (2H, m), 3.32 (2H, m), 2.29 (2H, m), 2.24 (2H, m), 2.17 (3H, s). MS m/z: 488.13, 490.15 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)[C:16](=[O:31])[C:15]3[C:10](=[CH:11][C:12]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[CH:13][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH3:39][Mg]Cl>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:22][CH:23]=3)[C:16]([CH3:39])([OH:31])[C:15]3[C:10](=[CH:11][C:12]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[CH:13][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=C1c2ccc(OC3CCCCO3)cc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: CC1(O)c2ccc(OC3CCCCO3)cc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C

Procedure:
To a solution of 90.0% 2-(4-iodophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one (104.891 g, 150.7 mmol, 1.0 equiv.) in THF (1.2 L) at 5° C., was added Methylmagnesium chloride 3.0 M solution in THF (160.000 ml, 480.0 mmol, 3.2 equiv.) by addition funnel over 30 minutes. The temperature did not rise about 8° C. during the addition. The reaction was removed from the ice bath and stirred at room temperature and stirred for another hour. TLC (20% ethyl acetate in hexanes) showed the reaction had no starting material. The solution was cooled in an ice bath, and carefully quenched with saturated ammonium chloride (35 mL). Ethyl acetate (1.2 L) and water (1.2 L) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EA (1 L). The combined organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield a pale yellow foam (111.26 g crude). This material was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:17])[N:13]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nnc1N
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2cc(C)nc12
Temperature: 100 °C

Procedure:
4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-ylamine (850 mg, 4.74 mmol), chloroacetone (0.415 ml, 5.22 mL) and 20 mL of ethanol are heated in the microwave at 110° C. for 35 minutes. Sodium bicarbonate (1.2 g, 14.2 mmol) is added, and the reaction mixture is heated in an oil bath at 100° C. overnight. The solvent is evaporate and the residue is taken up in ethyl acetate and washed three times with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated to a brown oil. The crude product is purified via silica gel chromatography using a hexane:ethyl acetate gradient. The title compound is an oil weighing 3.69 g (17.0 mmol, 84%). 1H-NMR (DMSO-d6), δ 7.34 (s, 1H); 6.84 (s, 1H); 2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712 (t, J=7.49 Hz, 6H) ppm. MS/ES+=219 (100%, M+2).
Reaction SMILES: [CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7].[N:19]1[N:20]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:22][CH:23]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:30]([C:25]1[C:24]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 70 mg, 0.37 mmol), EDC (177 mg, 0.92 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (126 mg, 0.922 mmol) and DIPEA (161 μl, 0.92 mmol) in dry DCM (1 ml) was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organics were washed with water (2×10 ml), brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% ethyl acetate/petrol) followed by a trituration in pentane/diethyl ether to afford the title compound. 1H NMR (400 MHz, DCM-d2) δ ppm 1.43 (s, 3H), 1.66-1.99 (m, 4H), 2.14-2.30 (m, 1H), 2.49-2.68 (m, 1H), 4.40-4.55 (m, 1H), 7.38-7.48 (m, 1H), 7.56 (br. s., 1H), 7.62-7.67 (m, 1H), 7.69 (br. s., 1H), 7.84 (s, 2H), 8.08-8.14 (m, 1H), 8.23 (br. s., 1H), 8.65-8.70 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:64]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N+:65]=[N-:66]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CCC(O)c2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(CCC(N=[N+]=[N-])c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the product from Step A (1.36 g, 5.6 mmol) in 20 mL of THF at 0° C. under Ar was added triphenylphosphine (1.8 g, 6.9 mmol), diethylazodicarboxylate (1.12 mL, 6.9 mmol) and diphenylphosphoryl azide (1.52 mL, 6.9 mmol). The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (2% EtOAc/Hexane) to provide the desired product as a nearly colorless gum.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Yield: 77.3 %

Procedure:
Methyl 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylate (980 mg, 2.9 mmol) and lithium hydroxide monohydrate (256 mg, 6.1 mmol) in THF (12 ml) and water (6 ml) were heated at 75° C. for 18 h. The THF was evaporated under vacuum and the aqueous adjusted to pH3 with hydrochloric acid (1M). The precipitate which formed was filtered off, washed with ether and dried under vacuum to give 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (720 mg, 77%). LCMS: retention time 3.33 min, MH+322.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH2:4][OH:5].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:15])([F:16])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH2:4][O:5][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
A mixture of 1,1,1-trifluoro-2-(4-ethoxyphenyl)propan-3-ol (0.4 g), 3-phenoxybenzyl bromide (0.45 g), tetra-n-butylammonium hydrogen sulphate (0.05 g) and aqueous sodium hydroxide solution (40% w/v, 5.0 cm3) was stirred at the ambient temperature for 6 hours after which it was partitioned between water and diethyl ether. The ethereal phase was separated, washed twice with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (0.75 g) was purified by chromatography on a silica gel column eluted with a mixture of hexane (23 parts by volume) and ethyl acetate (2 parts by volume) to yield 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy) propane (0.21 g) as a viscous oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10]C(C1C=NC=CC=1)=O)=[O:6].[I-:21].[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[I-:21].[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10][C:26]([CH:25]1[CH2+:24]=[CH:23][CH:2]=[CH:3][N:4]1[CH3:5])=[O:22])=[O:6]
Reactant: C1CCOC1
Reactant: O=NN(CCCl)C(=O)NCCOC(=O)c1cccnc1
Agent: [I-]
Product: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCCl)N=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 122 (1.5 g, 5 mmol) in 40 mL of tetrahydrofuran was treated with excess iodide. The mixture was stirred at 50° C. for 4 hours. The finely crystalline, yellow solid thus obtained (1.8 g, 82%) melted at 120°-121° C. and had the structure ##STR153## as confirmed by elemental analysis.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3cccs3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate and tributyl(thien-2-yl)-stannane, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.