Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>ClCCl>[CH3:8][S:9]([O:13][CH:14]([C:42]1[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 mmol of triethylamine and 2.00 mmol of methanesulphonyl chloride are added to a solution of 1.00 mmol of 4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is used without further purification in the next stage. Rf=0.43 (dichloromethane-methanol 95:5); Rt=4.46 (gradient I).
Reaction SMILES: [Na].Cl/[C:3](=[C:9]1\[CH2:10][CH2:11][C@@H:12]2[C@:26]\1([CH3:27])[CH2:25][CH2:24][C@@:23]1([OH:28])[C@H:13]2[CH2:14][CH:15]=[C:16]2[C@:21]1([CH3:22])[CH2:20][CH2:19][C:18]1([O:32][CH2:31][CH2:30][O:29]1)[CH2:17]2)/[C:4]([O:6][CH2:7]C)=[O:5].[OH2:33].Cl.[CH3:35]O>>[CH2:31]1[CH2:30][O:29][C:18]2([CH2:19][CH2:20][C@@:21]3([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]4[C@:23]3([OH:28])[CH2:24][CH2:25][C@@:26]3([CH3:27])[C@H:12]4[CH2:11][CH2:10]/[C:9]/3=[C:3](/[O:33][CH3:35])\[C:4]([O:6][CH3:7])=[O:5])[CH2:17]2)[O:32]1
Reactant: CO
Reactant: CCOC(=O)/C(Cl)=C1/CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Reactant: O
Agent: Cl
Agent: [Na]
Product: COC(=O)/C(OC)=C1\CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Temperature: 25 °C

Procedure:
To a solution of sodium (171 mg) in anhydrous methanol (10 ml) was added ethyl (20E)-20-chloro-3,3-ethylenedioxy-9α-hydroxypregna-5,17(20)-dien-21-oate (306 mg, as prepared in example 18), after which the reaction mixture was refluxed under nitrogen for 21 hours. The reaction mixture was cooled to room temperature. After adding methanol (20 ml) and water (10 ml) the mixture was neutralised with aqueous 5N hydrochloric acid. More water (30 ml) was added and a precipitate was formed. The solid was filtered, washed with water and dried to afford 46 mg of the title compound as a single isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cnc2ccccc2c1
Yield: 99 %

Procedure:
Using general procedure C, 3-bromoquinoline was coupled with 2-pyrrolidinone with the reaction time of 15 h. Chromatography gave 210 mg (99%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.24 (d, 1H, J=2.7 Hz), 8.45 (d, 1H, J=2.4 Hz), 8.08 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.66 (t,1H, J=7.7 Hz), 7.55 (t, 1H, J=7.5 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.69 (t, 2H, J=8.1 Hz), 2.28 (p, 2H, J=7.8 Hz).
Reaction SMILES: CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][N:29]([CH2:33][CH2:34][C@@:35]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:36](O)=[O:37])[C:28](=[O:44])[CH:27]=2)=[C:22]([F:45])[CH:21]=1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CC1CCCO1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][N:29]([CH2:33][CH2:34][C@@:35]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:36]([NH:53][O:52][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][O:46]3)=[O:37])[C:28](=[O:44])[CH:27]=2)=[C:22]([F:45])[CH:21]=1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (54 mL, 491 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (43.1 g, 245 mmol) were added to a solution of (2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (68.7 g, 164 mmol) in 2-methyltetrahydrofuran (1 L) and the reaction was stirred at rt for 2 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (28.8 g, 245 mmol) was added and the reaction was allowed to stir at rt for 1 h. The mixture was filtered and the filtrate was concentrated. The crude residue was purified via column chromatography using silica gel and eluting with 40% EtOAc in n-heptane (4 L) and EtOAc (6 L). The desired fractions were combined and concentrated to afford the title compound as a white gummy solid. (74.82 g, 88%). MS (LCMS) m/z 517.9 (M−1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: COc1cc(I)c(C(=O)O)cc1OC
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1cc(OC)c(OC)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzoic acid (24.6 g, 80 mmol), ethyl 2-aminoacetate hydrochloride (11 g, 88 mmol), EDCl (17 g, 88 mmol) and HOBt (14 g, 88 mmol) in dry DCM (500 mL) was added Et3N (55 mL, 400 mmol) dropwise at rt. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water, and thoroughly extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 3:1 (v:v) as eluent to give ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (29 g, 95%).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:26]([C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=5)[N:27]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc4c(c3)OC(F)(F)O4)ccc2=O)ccn1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=410.2 (M+H)+
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH2:39]([O:41][C:42]([C:44]1[S:48]C(N)=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]>CCCCCCC.C(OCC)(=O)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][C:4]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1sc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)nc1C

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (commercially available, CAS RN 7210-76-6) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Yellow solid (0.182 g; 67%). MS (ESI): m/z=652.12 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)(=[O:3])[CH3:2].C[OH:25]>O>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:6][C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:23])=[O:25])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc(-c2[nH]c(-c3ccncc3)c(C)c2C(C)=O)cc1
Reactant: CO
Solvent: O
Product: CC(=O)c1c(-c2ccc(S(C)=O)cc2)[nH]c(-c2ccncc2)c1C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-pyrrole (0.24 g, 0.74 mmol) in methanol (8 mL) was added a solution of NaIO4 (0.6 g) in water (16 mL) at room temperature. After stirring for 15 hours, the precipitates were collected by filtration. The filtrate was extracted with CH2Cl2—EtOH (10:1, 50 mL×2), dried over MgSO4, and concentrated ini vacuo. The solids were purified by flash chromatography eluting with CH2Cl2—EtOH (10:1) to provide the title compound (0.24 g, quantitative yield).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH2:11][NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]=[N+]=[N-])=[CH:25][CH:24]=2)[CH:15]=1)C1C=CC=CC=1.O>C(O)(=O)C.[Pd]>[NH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:35])=[O:8])=[O:34])=[O:33])=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: NCc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)O)c2)cc1
Yield: 56 %

Procedure:
296 mg of N-[m-[2-(α-azido-p-tolyl)acetamido]benzoyl]-β-alanine benzyl ester and 74 mg of Pd/C are stirred in 6 ml of acetic acid for 7 hours under hydrogen. After the addition of 3 ml of water the mixture is filtered and the filtrate is evaporated in a vacuum. The residue is taken up in water and the suspension is evaporated in a vacuum. The residue is triturated in methanol, filtered off under suction and dried. There are obtained 125 mg of N-[m-[2-(α-amino-p-tolyl)acetamido]benzoyl]-β-alanine (3:4 hydrate), m.p. 226° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:32])[F:31])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C(F)(F)F)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (1.97 g, 7.35 mmol) and 4-(trifluoromethyl)benzohydrazide (1.50 g, 7.35 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (1.13 g, 7.35 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (2.82 g, 14.7 mmol) at −45° C. followed by triethylamine (2.0 mL, 14.7 mmol). The reaction mixture warmed to room temperature and stirred for 23 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a off white solid (3.09 g, 92%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 10.71 (s, 1H), 10.31 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.67 (d, J=7.6 Hz, 1H), 5.31 (d, J=5.7 Hz, 1H), 4.14 (sextet, J=6.1 Hz, 1H), 3.94 (dd, J=5.7, 7.2 Hz, 1H), 2.30 (s, 3H), 1.28 (d, J=6.3 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:25][CH2:26]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: NCC1CCN(CCCCCCCCCCCCO)CC1
Product: OCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 32.5 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-(12-hydroxydodecyl)-piperidine (0.586 g, 2.0 mmol) according to procedure used for Example 2 to give 0.175 g of the title compound as an off-white solid (mp-110° C. (sinters) 166° C. (melts), Et2O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.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.Cl[Pd]Cl.[Cu](I)I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
A mixture of 3-bromobenzaldehyde (51.8 g), 1-undecyne (48.6 g), bis(triphenylphosphine)palladium(II)chloride (3.37 g), copper iodide (457 mg), and triethylamine (196 ml) in dry tetrahydrofuran (300 ml) was stirred for 4 hrs at 55° C. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate, and the solution was washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on 300 g of silica gel (1:4-ethyl acetate:hexane). The appropriate fractions were collected and evaporated. Distillation of a 40-g sample of the residue (81.3 g) gave 9.5 g (13%) of the product, bp 172°-174° C. (0.5 mm mercury).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:38])[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1=C(COCc2cc(=O)n(C)c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.1 %

Procedure:
A mixture of 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-pyrimidone (0.52 g), iodomethane (0.14 g) and potassium carbonate (0.14 g) in dimethylformamide (20 ml) was stirred at room temperature for 4 days and then evaporated. The residue was partitioned between chloroform and water and the organic layer washed twice with water, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallised from ethyl acetate to give the title compound (0.23 g), m.p. 202°-205° C. Found: C,53.42; H,4.87; N,10.49. C24H26Cl2N4O6 requires C,53.64; H,4.88; N,10.43%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C1CC(=O)N(c2ccc(Br)cc2)C1
Temperature: 130 °C
Reaction time: 0.83 h
Yield: 95.1 %

Procedure:
A mixture of 4-bromoaniline (8.6 g) and itaconic acid (6.5 g) was stirred at 130° C. for 50 minutes. After cooling, a n-hexane-ethyl acetate mixed solution was added to the resulting solid. The compound was collected by filtration to obtain the title compound (13.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>CCCCCC.C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[C:10]([Br:9])[CH:11]=2)[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Brc1cccc(Br)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
n-Bui (26.5 mL, 42.4 mmol, 1.6M in hexane) was added to a solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at −78° C. After stirred for 2 h at −78° C., the 3-bromobenzaldehyde (7.84 g, 42.4 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm up to r.t. and stirred at 30° C. for 12 h. The reaction was quenched with aq NH4Cl (100 mL). The mixture was extracted with dichloromethane (80 mL×5). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether ˜Petroleum ether: EtOAc=20:1) to afford 8.4 g of the title compound (24.5 mmol, 58%). LC/MS: [M−18+1]=325. 1HNMR (DMSO-d6), 400 MHz: δ 5.74 (d, 1H, J=4.0 Hz), 6.19 (d, 1H, J=4.4 Hz), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol)[from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][N:4]=1.Br[C:14]1[O:18][C:17]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.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>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:15]=2)=[N:4][CH:5]=1)#[N:10]
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: C[Sn](C)(C)c1ccc(C#N)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3cccc(C#N)c3)o2)nc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
In a similar fashion, Pd(PPh3)4 (10 Mg, 0.009 mmol) was added to a solution of 2-trimethylstannyl-5-cyano-pyridine (22.7 mg, 0.085 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (31 mg, 0.125 mmol) in toluene (1 mL) under argon. The resulting solution was stirred at 110° C. for 15 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 50% chloroform in hexane to 20% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with 50% dichloromethane in hexane afforded 5.3 mg (23%) of 3-(5-(5-cyano-2-pyridyl)-2-furyl)-benzonitrile (91% pure by GC/MS, contaminated by 9% dimer). 1H-NMR (CDCl3), δ (ppm): 8.85 (s, 1H), 7.87-8.05 (m, 5H), 7.52-7.63 (m, 3H), 7.36 (d, 1H), 6.95 (d, 1H), dimer impurity caused peak intensity to increase in region 8.00, 7.92, 7.49-7.57, plus 2 peaks additional peaks exactly overlapping with pure dimer @ δ (ppm): 6.87 (d) & 6.80 (d).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1csc2cncn12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1csc2cncn12
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice-cooled solution of 3.39 g of 3-hydroxymethylimidazo[5,1-b]thiazole in 22 ml of DMF were added 1.95 g of imidazole and 3.81 g of t-butyldimethylsilyl chloride. After the reaction mixture was reacted at room temperature for 6 hours, it was diluted with 150 ml of ethyl acetate, and washed three times with saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 5.83 g of 3-(t-butyldi methylsilyloxy)methylimidazo[5,1-b]thiazole.