Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O:21]CC=C)=[O:20])=[C:8]([C:10]3[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][CH3:18])[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].C(C(CCCC)C([O-])=O)C.[Na+:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClCCl.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:10]3[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][CH3:18])[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+:37]
Reactant: C=CCOC(=O)C1=C(c2cc(CC)n(CC)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1cc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1CC
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
Allyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-diethylpyrazol-3-yl)carbapen-2-em-3-carboxylate (267 mg) in dichloromethane (2 ml) and ethyl acetate (2 ml) under argon were treated with sodium 2-ethylhexanoate (135 mg), followed by triphenylphosphine (17.5 mg), followed by tetrakis(triphenylphosphine)palladium(0) (28.3 mg) and the mixture was stirred for 45 min. Diethyl ether (100 ml) was then added, and after stirring for 30 minutes the mixture was centrifuged. The residual solid was washed with diethyl ether, and dried under a stream of argon. The solid was then taken up in a small amount of water and chromatographed on DIAION HP20SS resin eluting with water, followed by water/THF mixtures; 2%, 3%, 4% and 6% THF. Fractions were monitored by HPLC, and those containing the product were combined, reduced in volume and freeze-dried to give sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-diethylpyrazol-3-yl)carbapen-2-em-3-carboxylate as a solid (169 mg); υmax(KBr) 1752, 1593, 1433, 1382, 1288, and 1258 cm−1; λmax(H2O)/nm 298 (ε/dm3 mol−1 cm−1 9,031), 260 (sh) (ε 5853); δ(D2O) 1.19 (t, J 7.6 Hz), 1.27 (d, J ca. 6.8 Hz), 1.28 (d, J ca. 7.3 Hz) (together 9H), 2.60 (2H, q, J 7.5 Hz), 3.18 (2H, d, J 9.8 Hz), 3.46 (1H, dd, J 2.7 & 5.9 Hz), 4.05 (2H, q, J 7.2 Hz), 4.14-4,26 (2H, m), 6.48 (1H, s) ppm; [Found (electrospray ms) m/z 342 (MH)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH2:13])[CH3:12]>O>[CH2:11]([NH:13][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1)[CH3:12]
Reactant: CSc1nc(C)cc(Cl)n1
Reactant: CCN
Solvent: O
Product: CCNc1cc(C)nc(SC)n1
Temperature: 50 °C
Yield: 90 %

Procedure:
To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added 30 mL of a solution of 70% ethylamine in water. The reaction mixture was heated to 50° C. for 3 h. After completion, excess ethylamine was evaporated on rotary evaporator under vacuum. The solid was filtered and dried under vacuum to afford N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 90% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=1[C:59]#[N:60])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: N#Cc1ccccc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z=595.0.
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[C:13]([O:16]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)=[C:28]([F:37])[C:27]=1[F:38])C1C=CC=CC=1>[C].[Pd].C1COCC1>[CH:34]1([CH2:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]3[O:39][C:9]4[C:14]([F:15])=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=4[N:24]=3)=[C:27]([F:38])[C:28]=2[F:37])[CH2:35][CH2:36]1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1OCc1ccccc1)c1ccc(OCC2CC2)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A mixture of N-(2,4-bis(benzyloxy)-3-fluorophenyl)-4-(cyclopropylmethoxy)-2,3-difluorobenzamide (4.40 g), 10% palladium-carbon (containing water (50%), 3.50 g) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure, and the solid was washed with diethyl ether. To a suspension of the obtained solid, hexachloroethane (4.88 g) and triphenylphosphine (5.41 g) in acetonitrile (40 mL) was added triethylamine (3.45 mL) at 0° C., and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.37 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([C:12](=[O:26])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([C:12](=[O:26])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(NC(=O)C(=O)c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C(=O)Nc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 22e, by reacting 0.4 g (0.88 mmol) of methyl 4-[2-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthyl)-2-oxoacetylamino]benzoate with 0.074 g (1.77 mmol) of lithium hydroxide hydrate, a yellow solid is obtained (0.21 g; yield=56%; m.p.=255° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:30][C@H:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: C[C@H](N)c1ccc2ccccc2c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](Nc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (S)-(−)-1-(2-naphthyl)ethylamine and DBU in DME. ES-MS m/e(%): 356 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]=[O:18])[CH:19]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Yield: 90 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), 5-hydroxy-2-methoxybenzaldehyde (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 17 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.01 g, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=[CH:7][C:6]=1B(O)O.Br[C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH:26]=[CH:27][C:28]([OH:30])=[O:29]>CCCCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:32]1[CH:31]=[C:25]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:23][CH:33]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: COCOc1c(B(O)O)ccc2c1C(C)(C)CCC2(C)C
Solvent: CCCCCCC
Product: COCOc1c(-c2cccc(C=CC(=O)O)c2)ccc2c1C(C)(C)CCC2(C)C
Yield: 61.2 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 3.4 g (11.6 mmol) of 1-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene-boronic acid with 1.32 g (5.8 mmol) of 3-bromocinnamic acid, trituration in heptane gave 1.4 g (62%) of 3-[3-(1-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid in the form of a white powder having a melting point of 188°-9° C.
Reaction SMILES: IC1C=CC(O[C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=CC=1.C(OCC)(=O)C=C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>C(N(CC)CC)C.C(#N)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: COc1cc2ncnc(Oc3ccc(I)cc3)c2cc1OC
Agent: [Pd+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C
Yield: 136.7 %

Procedure:
Palladium (II) acetate (11 mg, 0.05 mmol) was added to a solution of 4-(4-iodophenoxy)-6,7-dimethoxyquinazoline (205 mg, 0.50 mmol), ethyl acrylate (50 mg, 0.50 mmol) and tri(o-tolyl)phosphine (30 mg, 0.10 mmol) in a mixture of triethylamine (3 ml) and acetonitrile (9 ml) and the reaction heated at reflux for 16 hours under an inert atmosphere. The reaction was cooled to ambient temperature, poured into water (30 ml), diluted with ethyl acetate (25 ml) and filtered through celite. The organic layer was separated, the aqueous was extracted with ethyl acetate (2×25 ml) and the combined organic layers were dried over magnesium sulphate before solvent evaporation in vacuo. Purification by flash chromatography on silica gel, eluting with ethyl acetate/isohexane (1:1), yielded 4-(4-(2-carboethoxy)ethenyl)phenoxy)-6,7-dimethoxyquinazoline (130 mg, 68% yield) as a cream solid:
Reaction SMILES: ClC1C=CC([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)CC)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58]4(OCC(C)(C)C[O:59]4)[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH2:48][CH3:49])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CC[C@@H](c1ccc(Cl)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC[C@@H](c1ccc(Cl)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-chloro-phenyl)-propylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(4-chloro-phenyl)-propyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 68% of theory; LC (method 6): tR=1.32 min; Mass spectrum (ESI+): m/z=336/338 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:10][CH:9]=1)=[O:5].[ClH:42]>C(Cl)Cl>[ClH:42].[ClH:42].[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([CH2:28][NH2:29])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(C(=O)OCc2ccc([C@@H](CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)OCc2ccc([C@H](CN)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 9 h

Procedure:
(R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dihydrochloride (E197-R) was prepared from E145-R according to the scheme in FIG. 6. To (S)-4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145-R) in CH2Cl2 was added HCl (4 N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dihydrochloride (E197-R). Analysis by chiral HPLC (Chiralpak AS-H, eluent:90:10:0.1 EtOH:H2O:diethylamine) showed enantiomeric excess >98%.
Reaction SMILES: IC1SC(I)=CC=1.C[Si](C#C)(C)C.C[Si]([C:18]#[C:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:23][CH:24]=1)(C)C.[OH-].[K+]>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(N(CC)CC)C>[C:19]([C:20]1[S:21][C:22]([C:25]#[CH:26])=[CH:23][CH:24]=1)#[CH:18]
Reactant: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C[Si](C)(C)C
Agent: Ic1ccc(I)s1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1ccc(C#C)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
To a 250 mL flask were added 2.5 g of 2,5-diiodothiophene (7.44 mmol), 100 mg of Cul, and 220 mg of Pd(Ph3P)2Cl2 under nitrogen. Then 100 mL of triethylamine (TEA) and 5.0 mL of trimethylsilylacetylene (3.40 g, 35 mmol) were injected. The reaction mixture was allowed to stir at room temperature for 12 hours. The precipitate was removed by filtration and the solvent of the filtrate was evaporated. The crude intermediate, i.e. 2,5-bis(trimethylsilylethynyl)thiophene, was purified by column chromatography and thus hydrolysed with 3 g KOH (53.6 mmol) in 70 mL methanol for 2 hours. The solution was poured into a large amount of water, and extracted with diethyl ether twice. The resultant solution was washed with water three times, dried over magnesium sulphate, and then the solvent was removed under reduced pressure to give 2,5-diethynylthiophene as a pale yellow liquid (0.71 g, 72%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>COCCO>[C:22]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=1)#[N:23]
Reactant: COC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (46 mg, 0.15 mmol), β-alanine (674 mg, 7.57 mmol) and NaOMe (327 mg, 6.05 mmol) in 2-methoxyethanol (12 mL) was refluxed for 1.5 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a pale pink solid. MS: (−) m/z 360.07 (M−1).
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH3:20][C:21](=C)[CH2:22]O>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][C:21]([CH3:22])=[CH2:20])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: C=C(C)CO
Product: C=C(C)COC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (4.0 g., 15.7 mmoles) was stirred with 20 ml. of 2-methyl-2-propen-1-ol for 20 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water, and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give (2-methyl-2-propen-1-yl) 9-xanthenyl ether, b.p. 116°C. at 0.15 mm.
Reaction SMILES: [Cl:1][C:2]1[C:17]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:16][CH:15]=[C:14]([F:25])[C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[OH-].[Ba+2].[OH-].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:17]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:20])=[O:21])=[CH:16][CH:15]=[C:14]([F:25])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Ba+2]
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
Benzyl 2-chloro-6-fluoro-3-(propylsulfonamido)benzoate (174.5 mg, 0.4523 mmol) was dissolved in 3:1 dioxane:water (7.5 mL) and treated with barium hydroxide (100.7 mg, 0.5879 mmol). The reaction mixture was heated to 80° C. for 16 hours and then allowed to cool to ambient temperature. The mixture was acidified to a pH of 0 with concentrated HCl. The reaction mixture was allowed to stir for 10 minutes, after which the pH was adjusted to a pH of 4 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (2×). The extracts were washed with water (2×) and brine (1×), dried over sodium sulfate, and concentrated to afford 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (75.7 mg, 0.2560 mmol, 56.6% yield). MS (APCI-neg) m/z=293.9 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH3:16][Zn]C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd]Br>[F:8][C:6]1[CH:7]=[C:2]([CH3:16])[CH:3]=[C:4]([F:15])[C:5]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C[Zn]C
Reactant: COC(=O)C(C)c1c(F)cc(Br)cc1F
Agent: Br[Pd]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)C(C)c1c(F)cc(C)cc1F
Yield: 77.4 %

Procedure:
Compound (30b) (5.4 g, 19.3 mmol) and dimethyl zinc (2M-solution in toluene, 38.7 mL, 77.4 mmol), and a solution (40 mL) of trans-dibromobis(triphenylphosphine)palladium(II) [trans-Pd(PPh3)2Br2] (0.085 g, 5.6 mol %) in 1,4-dioxane (40 mL) were treated in the same manner as in (k) above. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.2 g (77%) of compound (31b) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[O:30])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: O=C(Cl)c1cccs1
Product: O=C(c1cccs1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 34 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and 2-thiophenecarbonyl chloride as the starting materials in 34% yield. LCMS for C22H17ClN5OS (M+H)+: m/z=434.0.
Reaction SMILES: C[O-].[Na+].[I-].[K+].[CH3:6][C:7]1[CH:8]=[C:9]([OH:15])[CH:10]=[C:11]([CH3:14])[C:12]=1[Cl:13].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>CO.C1C=CC=CC=1.O>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([CH3:14])[C:12]=1[Cl:13])[O:15][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Cc1cc(O)cc(C)c1Cl
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(Oc1cc(C)c(Cl)c(C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 3.92 g of 3,5-dimethyl-4-chlorophenol. After one hour, a solution of 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene is added. The solution is refluxed overnight. After cooling to room temperature the mixture is poured into 100 ml of water and extracted with two 60 ml portions of ether. The combined extracts are washed with two 50 ml portions of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent affords a yellow oil which is chromatographed on 100 g silica gel and eluted with 400 ml of benzene. Evaporation of the solvent under vacuum gives the product as a colorless oil.