Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ncc(C=O)c(C)c1OCc1cccc(C#N)c1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 42.3 %

Procedure:
The reductive amination of 3-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (27) (7.0 g, 26.3 mmol) and 4-aminobenzonitrile (10.2 g, 86.3 mmol), as described in Example 21, gave 4-{[5-(3-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-benzonitrile (32) (4.1 g, 68% yield) as a colorless solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25](=[O:26])[NH:55][CH:50]([CH3:51])[CH3:49])[CH:23]=4)[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)O)c3)nc12)C(=O)N1CC(C#N)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (70 mg, 0.13 mmol) and HATU (53.4 mg, 0.14 mmol) in DMF (1.5 mL) was added isopropylamine (44 μL, 0.51 mmol). The reaction mixture was stirred at room temp for 4 h then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was chromatographed with 50% to 100% EtOAc/hexanes to isolate 52 mg (69%) of 2-(3-isopropylcarbamoyl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white foamy solid.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C(OC(=O)[CH2:8][C:9]1[C:10]([Cl:23])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:14]2)C.C[O-].[Na+]>CN(C)C=O.O>[Cl:23][C:10]1[C:9]([CH2:8][C:1]([NH2:3])=[O:2])=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)nc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 105 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Formamide (118 mg, 2.62 mmol, 3.35 equiv) was added to a solution of (7-chloro-2-dimethylaminomethyl-quinolin-8-yl)-acetic acid ethyl ester (240 mg, 0.78 mmol) in N,N-dimethylformamide (1.0 ml). The solution was heated to 105° C., and then sodium methoxide (5.4 M in MeOH, 0.14 ml, 0.78 mmol, 1.0 equiv) was added dropwise over 20 minutes. After 1 hour, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc and CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of CH2Cl2/MeOH 96:4 to 60:40) afforded the title compound (161 mg, 74%) as a white solid. 1H NMR (400 MHz, d6-DMSO): δ=8.35 (d, J=8.9 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.41 (br s, 1H), 6.88 (br s, 1H), 4.26 (s, 2H), 3.69 (s, 2H), 2.21 (s, 6H). MS (ES+): 278.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]2.[F:18][CH:19]([F:40])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>CO>[F:40][CH:19]([F:18])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]2[CH2:33][CH2:32][N:31]([CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]4)[CH2:30][CH2:29]2)=[CH:25][CH:26]=1
Reactant: NC(=O)c1cc2c(OCC3CO3)cccc2[nH]1
Reactant: FC(F)Oc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CO
Product: NC(=O)c1cc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccc(OC(F)F)cc4)CC3)cccc2[nH]1
Temperature: 80 °C

Procedure:
3.45 g of 4-(2,3-epoxypropoxy)-1H-indole-2-carboxamide and 4.70 g of 1-((4-difluoromethoxyphenyl)phenylmethyl)piperazine are dissolved at 40° C. in 75 ml of methanol. The mixture is then concentrated to dryness in vacuo, the syrupy residue is heated at 80° C. for 15 minutes and, after cooling, the solidified product is triturated with hexane and filtered off with suction.
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26](O)=[O:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]([N:5]([CH2:25][C:26](=[O:27])[N:31]([CH3:32])[CH3:30])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with dimethylamine hydrochloride (CAN 506-59-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=425.5 [MH+].
Reaction SMILES: [CH2:1]([C:5]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:17]2[CH:16]=[C:15]([C:18]3[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[C:38]([CH2:40][C:41]([OH:43])=[O:42])#[N:39]>C(#N)C.N1CCCCC1>[C:38]([C:40](=[CH:23][C:21]1[S:22][C:18]([C:15]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=4)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:34][CH2:35][CH2:36][CH3:37])[C:17]=3[CH:16]=2)=[CH:19][CH:20]=1)[C:41]([OH:43])=[O:42])#[N:39]
Reactant: N#CCC(=O)O
Reactant: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=O)s3)ccc1-2
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=C(C#N)C(=O)O)s3)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:40])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH:38]=[O:39])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(N)(=O)(=O)[OH:42].Cl([O-])=O.[Na+]>C(O)(=O)C.O>[C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:31]1[C:19]2[CH2:18][C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:40])[CH2:9][CH2:10]3)[C:27]3[C:22]([O:21][C:20]=2[CH:28]=[CH:29][CH:30]=1)=[N:23][CH:24]=[CH:25][CH:26]=3)([OH:42])=[O:39]
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccccc1-c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of the product of step 1 (270 mg) in acetic acid (2.2 ml) and water (0.5 ml) were added amidosulfuric acid (67 mg) and sodium chlorite (68 mg) in water (0.1 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was distilled off under reduced pressure into half volume. The residue was neutralized with 1N sodium hydroxide. The precipitation was filtered and washed with water to give the titled compound (80 mg).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[CH:12]=[O:13].Cl>O>[CH:12]([C:11]1[CH:14]=[C:15]([CH3:18])[C:16]([O:17][CH2:4][C:5]([OH:7])=[O:6])=[C:9]([CH3:8])[CH:10]=1)=[O:13]
Reactant: O=C(O)CBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C=O)cc(C)c1OCC(=O)O
Temperature: 100 °C
Reaction time: 24 h
Yield: 15.2 %

Procedure:
A solution of sodium hydroxide (2.53 g, 63.25 mmol) in water (65 mL) was added to a mixture of bromoacetic acid (5.27 g, 37.95 mmol) and 3,5-dimethyl-4-hydroxy-benzaldehyde (1.9 g, 12.65 mmol) in water (30 mL). The reaction mixture was stirred at 100° C. for 24 h. The solution was acidified to pH ˜2 with conc. HCl. The brown solid was filtered off, washed with water, dried under vacuum, and purified by column chromatography to give (4-formyl-2,6-dimethyl-phenoxy)-acetic acid as a light brown solid (0.40 g). To a solution of 2-amino-4,6-dimethoxybenzamide (0.150 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added (4-formyl-2,6-dimethyl-phenoxy)-acetic acid (0.159 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.150 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. for 3 h. it was then cooled to room temperature and water (40 mL) was added. A yellow precipitate was formed and filtered off, washed with water and a small amount of methanol. Triturated with 10% methanol in ether to give 0.084 g of compound, which was further purified by preparative HPLC to give 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid (47 mg, 13%) as a white solid. Selected data: MS (ES) m/z: 384.0; MP 270-272° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]([NH:53][C:54]2[CH:55]=[C:56]([C:60]3[N:69]=[C:68]([NH:70][C:71]4[CH:72]=[C:73]5[C:77](=[CH:78][CH:79]=4)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]5)[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(O)CN1CCOCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (96 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate ( ) (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture and stirred for 1.5 h. Added two more 0.5 equivalents of activated acid while stirring 1.5 hr between each addition. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [I:1][C:2]#[C:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[I:1][C:2]1[N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[N:18][C:3]=1[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: IC#Cc1ccsc1
Product: Ic1c(-c2ccsc2)nnn1Cc1ccccc1

Procedure:
Synthesized from 3-(iodoethynyl)thiophene and benzylazide using one-pot/two-step general procedure, 1.24 g, 3.38 mmol, 81%; mp=125-127° C. (dec.); IR (υ[cm−1]) 3025, 1496, 1455, 1354, 1318, 1230, 1211, 1072, 1008, 783, 717; 1H NMR (600 MHz, CDCl3) δ=7.94 (d, J=1.6, 1H), 7.75 (d, J=4.7, 1H), 7.39 (dd, J=4.7, 3.0, 1H), 7.36-7.29 (m, 3H), 7.29-7.25 (m, 2H), 5.64 (s, 2H); 13C NMR (151 MHz, CDCl3) δ=147.3, 134.5, 131.2, 129.1, 128.7, 127.9, 126.8, 126.1, 122.9, 76.0, 54.5; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C13H11IN3S, 367.9713; found 367.9713.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N+:26]([O-])=O)[CH2:20][CH2:21][C:22]([O:24]C)=O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:29][CH:30]([CH3:31])[CH3:32])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][CH2:21][C:22](=[O:24])[NH:26]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)CCC(c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CCC(=O)N3)cc2)c(C)c1
Temperature: 25 °C

Procedure:
To a suspension of palladium on carbon (22.09 mg, 0.208 mmol) in ethanol (5 mL) stirred under nitrogen at room temperature was added a solution of methyl 4-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)-4-nitrobutanoate (96 mg, 0.208 mmol) in ethanol (5 mL) dropwise. The flask was carefully filled with hydrogen and the reaction mixture was stirred at 20° C. for 2 hours. LCMS analysis showed disappearance of starting material. The reaction mixture was filtered through celite under an atmosphere of nitrogen and the filtrate evaporated in vacuo to give a yellow gum. The crude was purified by mass directed autoprep (formic acid modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 1.01 mg. LCMS [LCMS1] Rt 1.17 min, m/z (ES+) 400 (M+H, weak) 442 (M+MeCN+H)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C
Yield: 56.1 %

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.48 g, 1.1 mmol), methanamine (1.5 ml, 33% in EtOH, 4 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography (MeOH/EtOAc) gave the title compound (0.18 g). The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 262° C. MS m/z (rel. intensity, 70 eV) 291 (M+, 43), 113 (57), 85 (80), 70 (bp), 63 (84), 50 (60) [α]=−61° (MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:19]2[CH:18]=[CH:17][C:16]3[O:12][CH2:13][CH2:14][C:15]=3[CH:20]=2)=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Reaction time: 2 h
Yield: 73 %

Procedure:
5-bromo-2-chloro-benzoyl chloride 2a (10.8 g, 42.5 mmol) was dissolved in 100 mL dichloromethane, followed by addition of 2,3-dihydrobenzofuran 5a (5.11 g, 42.5 mmol) and addition of aluminum trichloride (6.8 g, 51.0 mmol) in batch. The reaction mixture was stirred for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound (5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanone 5b (10.47 g, white solid), yield: 72.9%. MS m/z (ESI): 339.0 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, 1H), 7.58 (dd, 1H), 7.53 (dd, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 6.81 (d, 1H), 4.68 (t, 2H), 3.26 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6](Cl)[N:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.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.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2C#Cc2ccccc2)ccc1=O
Temperature: 80 °C
Yield: 89.8 %

Procedure:
A mixture of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (200 mg), ethynylbenzen (331 mg), NEt3 (658 mg), triphenylphosphine (17 mg), CuI (6.2 mg), and PdCl2(PPh3)2 (23 mg) in DMF (2 ml) was heated at 80° C. for 18 hours. Water (20 ml) and EtOAc (20 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH (97:3). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(phenylethynyl)-2-pyrazinecarboxamide (218 mg) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC[CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1>[OH-].[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: BrCCc1ccsc1
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(C(=O)O)cc(SCc2ccsc2)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.5 g) in 0.5 N sodium hydroxide (100 ml), a solution of 3-bromoethylthiophene (3.5 g in benzene (20 ml)) is added. The reacton mixture is stirred for 2 hours at room temperature. After extraction with additional benzene, the aqueous layer is acidified by addition of 4 N hydrochloric acid to precipitate 5-amino-4-phenoxy-3-(3-thienylmethylthio)benzoic acid. After collection by filtration, recrystallisation from aqueous ethanol and drying, the compound is obtained with a melting point of 153°-155°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>[Cu]I.O1CCCC1.CCN(CC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ncc(I)nc2-c2ccc(F)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3-bis(4-fluorophenyl)-5-iodopyrazine (400 mg, 1.02 mmol, 1.00 equiv), methyl acrylate (1.8 g, 20.93 mmol, 20.62 equiv), CuI (193 mg, 1.02 mmol, 1.00 equiv), Pd(PPh3)Cl2 (285 mg, 0.41 mmol, 0.40 equiv), and tetrahydrofuran/Et3N (2/1 mL) was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:40)) resulting in 120 mg (28%) of (E)-methyl 3-(5,6-bis(4-fluorophenyl)pyrazin-2-yl)acrylate as a grey solid.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10]C)=[O:9])[N:2]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CO.[OH-].[Li+]>C1COCC1>[C:15]([O:14][C:12]([N:2]1[C@H:3]([C:8]([OH:10])=[O:9])[C@H:4]2[CH2:7][C@@H:1]1[CH2:6][CH2:5]2)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of (1S,3S,4R)-2-tert-butyl 3-methyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.67 g, 6.54 mmol) in THF:MeOH (41 mL:13 mL) was added aqueous Lithium hydroxide (1M, 8.2 mL, 8.2 mmol) and the reaction was allowed to stir at room temperature overnight. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.36 g, 86%). 1H NMR (400 MHz, Methanol-d4) δ 6.43 (s, 1H), 5.84 (s, 1H), 5.74 (d, 1H), 4.34 (s, 1H), 3.36-3.18 (m, 3H), 3.17-3.06 (m, 3H), 3.02 (s, 3H), 2.97 (s, 6H).