Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:23]#N)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.C1C[O:28][CH2:27]C1.[CH:30](OCC)=O>>[C:23]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:21][CH:20]([CH:27]=[O:28])[C:19](=[O:22])[CH2:18][CH2:17]1)#[CH:30]
Reactant: CCOC=O
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1oc1ccccc12
Reactant: C1CCOC1
Product: C#CC1(c2ccc(OC)c3oc4ccccc4c23)CCC(=O)C(C=O)C1
Reaction time: 0.25 h

Procedure:
At 0° C., to a solution of the cyclic ketone 1-(4-methoxy-dibenzofuran-1-yl)-4-oxo-cyclohexane carbonitrile (0.5 g, 0.00156 mol) (as obtained in example 2) in THF (15 ml) sodium methoxide (0.093 g, 0.0017 mol) was added and the reaction mass was stirred for 15 min. Then ethyl formate (0.15 ml, 0.0018 mol) was added at 0° C., and the reaction mass was refluxed for 1 hr. Once product has formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. The product 5-ethynyl-5-(4-methoxy-dibenzofuran-1-yl)-2-oxo-cyclohexanecarbaldehyde was isolated by column chromatography. Yield 0.250 g (46%)
Reaction SMILES: [CH3:1][O:2][CH2:3][S:4][CH:5]1[N:8]([C:9](=[C:23](O)[CH3:24])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:26])[CH:6]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CS(Cl)(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[Br:49]N1C(=O)CCC1=O>O1CCCC1.O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][S:4][CH:5]1[N:8]([C:9](=[C:23]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:24][Br:49])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:26])[CH:6]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C1COCCN1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCSC1C(NC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(C)O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCSC1C(NC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(CBr)N1CCOCC1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
One dissolves p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-hydroxyethylidene)-acetate (1.06 g) in tetrahydrofuran (10 ml), cools to -40° C. under nitrogen atmosphere, adds triethylamine (489 mg) dissolved in tetrahydrofuran (1 ml) and methanesulfonyl chloride (252 mg) dissolved in tetrahydrofuran (1 ml), and stirs for 30 minutes at -40° C. and for 45 minutes at 0° C. To this solution, one adds morpholine (209 mg) dissolved in tetrahydrofuran (1 ml), keeps at 0° C. for 2 hours, adds N-bromosuccinimide (392 mg), keeps at 0° C. for 1.5 hours, adds water, and removes the separated oily material, and extracts with ethyl acetate. The extract solution and the removed oily material is combined, dried over magnesium sulfate, and evaporated. Purification of the obtained residual oil (1.4 g) by chromatography over silica gel containing 5% water (20 g) gives p-nitrobenzyl α-[4 -methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-morpholino-2-bromoethylidene)acetate (700 mg; Yield: 52%) and p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-acetidin-1-yl]α-(1-morpholinoethylidene)acetate (170 mg; Yield: 14%).
Reaction SMILES: [CH2:1]([N:3]([CH2:67][CH3:68])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:47]2[CH:52]=[C:51]([C:53](=[O:66])[NH:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=3)[CH:50]=[CH:49][N:48]=2)[CH:5]=1)[CH3:2].[CH3:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][N:91]1[CH2:96][CH2:95][NH:94][CH2:93][C:92]1=[O:97]>>[CH3:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][N:91]1[CH2:96][CH2:95][N:94]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([S:35]([NH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][CH2:19][C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:67][CH3:68])=[CH:5][C:6]=3[C:47]3[CH:52]=[C:51]([CH:50]=[CH:49][N:48]=3)[C:53]([NH:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=3)=[O:66])=[O:12])(=[O:37])=[O:36])=[CH:39][CH:40]=2)=[O:43])[CH2:93][C:92]1=[O:97]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)O)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: COCCOCCOCCOCCOCCOCCOCCN1CCNCC1=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)N4CCN(CCOCCOCCOCCOCCOCCOCCOC)C(=O)C4)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 4-(N-(15-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-3,6,9,12-tetraoxapentadecyl)sulfamoyl)benzoic acid 272a by following the procedure described in Example 272 using 1-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)piperazin-2-one 135c.5 as the amine component in this coupling. MS (ES, m/z) 1368.4 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.[I-].[K+]>CC(C)CC(=O)C>[OH2:7].[OH2:29].[ClH:2].[ClH:1].[O:29]=[C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:3][CH2:4][NH:5][C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[O:7])[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22]1
Reactant: O=C(NCCCl)c1ccccn1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccn1

Procedure:
A mixture of 2.2 parts of N-(2-chloroethyl)-2-pyridinecarboxamide hydrochloride, 6.6 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 1.66 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the precipitated product is filtered off and dissolved in water. The solution is alkalized with sodium carbonate and the product is extracted three times with 4-methyl-2-pentanone. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the element is evaporated. The residue is converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane (1:1 by volume), yielding 2 parts of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-ethyl}-2-pyridinecarboxamide dihydrochloride dihydrate; mp. 165.7° C.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:12][P+:13]([CH2:18]O)([CH2:16]O)[CH2:14]O.[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]=[C:22]1[N:24]([CH3:25])[CH2:16][P+:13]2([CH2:12][N:24]([CH3:25])[C:22](=[O:23])[N:21]([CH3:20])[CH2:14]2)[CH2:18][N:21]1[CH3:20]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: O=S(=O)([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 111.2 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium benzenesulfonate (31.23 g, 0.1 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (100 ml), following Example 19, gave 46.30 g of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro[5.5]undecane benzenesulfonate (II, R=R'=CH3, X=SO3C6H5) as a caramel-colored, low-melting solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([O:33]CC)=[O:32].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:27])[F:26])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:30][C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
(±)-(E)-ethyl 2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (13 mg, mmol) was dissolved in THF (0.4 mL) and MeOH (0.8 mL). A solution of LiOH.H2O (10 mg) in water (0.4 mL) was added. The mixture was stirred at rt for 5 d. The reaction mixture was submitted directly to preparative HPLC to afford (±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (6 mg, %) as a solid. LC-MS Method 1 tR=1.92, min, m/z=522, 524.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[S-:8].[Na+].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[S:8][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Fc1cncc(F)c1[S-]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Yield: 66.9 %

Procedure:
Prepared according to the procedure described for example 18, sodium 3,5-difluoropyridine-4-thiolate (529 mg, 3.6 mmol) reacted with methyl 5-chloro-4-nitro-thiophene-2-carboxylate (800 mg, 3.6 mmol) to afford the titled product (800 mg, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.91 (2H, s), 8.18 (1H, s), 3.85 (3H, s). MS m/z: 333.04 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C)=O.C(=O)=O.C([O:35][B:36](OC(C)C)[O:37]C(C)C)(C)C.Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[B:36]([OH:37])[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 4-benzyloxy-3-bromobenzotrifluoride (4.48 g, 13.54 mmol) in tetrahydrofuran (100 ml) was cooled to −100° C. (diethyl ether/liquid nitrogen) with stirring under nitrogen. 1.6 M n-butyllithium in hexanes (9.3 ml, 14.89 mmol) was added over 20 mins. at −100° C. and the mixture warmed to −78° C. (acetone/Drikold) and stirred for 1 h. Triisopropylborate (7.64 g, 9.38 ml, 40.66 mmol) was added dropwise at −78° C. and the reaction stirred and allowed to warm to room temperature over 1.5 h. 1M Hydrochloric acid (100 ml) was added and the mixture stirred vigorously for 1 h. The layers were separated and the aqueous layer extracted with diethyl ether (50 ml). The combined organic phases were washed with water, dried (MgSO4) and the solvent removed in vacuo. The yellow waxy solid was flash chromatographed (silica gel, 4-20% EtOAc-isohexane) and the product triturated with hexane. The white solid was filtered and dried in vacuo to give the title compound (1.53 g, 38%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:7][N@:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O.[C-:25]#[N:26].[K+].ClCCl>CS(C)=O>[C:25]([CH2:7][C@H:5]([NH:6][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][C:3]1[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:2]=1[F:1])#[N:26]
Reactant: [C-]#N
Reactant: O=C(OCc1ccccc1)N1CC1Cc1cc(F)c(F)cc1F
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CC[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
15.78 g of (R)-benzyl 2-(2,4,5-trifluorobenzyl)aziridine-1-carboxylate was dissolved in 63.2 mL of dimethylsulfoxide and 15.8 mL of water in 250 mL flask; then 7.89 g of silicagel was added thereto. 6.40 g of potassiumcyanide was slowly added to the reaction solution, and the resulting reaction solution was stirred for 24 hours at 50° C. The reaction solution was cooled to room temperature, and then 160 mL of dichloromethane and 800 mL of water were added to the cooled reaction solution in order. An organic layer was isolated; washed with 80 mL of water in twice; dehydrated with sodium sulfate; and then concentrated under reduced pressure. 80 mL of diisopropylether was added to the concentrated residue and then the resulting concentrated residue was stirred for 1 hour at room temperature. The resulting solid was decompression-filtered and vacuum-dried to obtain 14.66 g of a title compound.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[C:10]([CH:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](OCC)=[O:15])(=O)[CH3:11]>CCO>[CH3:7][C:6]1[NH:9][C:14](=[O:15])[C:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:11])[N:8]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nc(C)[nH]c1=O
Yield: 26.9 %

Procedure:
A mixture of NaOEt (0.069 mol) in EtOH (prepared from 1.6 g of Na in 100 mL of EtOH), acetamidine hydrochloride (6.5 g, 0.069 mol), and diethyl 2-acetylsuccinate (15.0 g, 0.069 mol) was heated under reflux for 16 h. The mixture was concentrated, taken up in water (50 mL), and acidified with 2N HCl (12 mL). The aqueous mixture was extracted with CH2Cl2, and the extracts were dried (MgSO4) and concentrated. Trituration with ether gave 3.9 g (27%) of product as a white solid, mp 175°-177° C.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C@H:35]([C:42]#[CH:43])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:34][C@H:35]([C:42]#[CH:43])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:17])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: C#C[C@@H](N)CC(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: C#C[C@H](CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 1 h

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride was added to dry DMF (35 ml) followed by N-methylmorpholine (0.39 g, 1 eq.) and isobutyl chloroformate (0.53 g, 3.9 mmol) at 25° C. The mixture was stirred for 5 min. (S)-ethyl 3-amino-4-pentynoate was added followed by diisopropylethylamine and a catalytic amount of dimethylaminopyridine. After 1 hour, the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography to give (3S)-ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:11]3[N:12]=[CH:13][S:14][CH:15]=3)=[N:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28](#[N:30])[CH3:29]>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:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][C:9]([C:11]4[N:12]=[CH:13][S:14][CH:15]=4)=[N:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:28]=[N:30][C:2]([NH2:7])=[N:3][CH:4]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: Clc1nc(N2CCOCC2)c2sc(-c3cscn3)nc2n1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(-c4cscn4)nc3n2)cn1

Procedure:
5-Chloro-7-morpholino-2-(thiazol-4-yl)thiazolo[4,5-d]pyrimidine, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 138. MS data: (ESI+): MH+ 399.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)(C)(C)C.[ClH:25]>ClCCl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:23][O:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH:21]=1
Reactant: COc1cc(NCCCNC(=O)OC(C)(C)C)nc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(NCCCN)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of [3-(4-methoxyquinolin-2-ylamino)propyl]carbamic acid tert-butyl ester (3.10 g, 9.35 mmol) in anhydrous dichloromethane (20 ml) was treated with 4N HCl in 1,4-dioxane (10 ml). It was stirred at ambient temperature for 2 hours then was evaporated under reduced pressure to give N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine dihydrochloride (2.81 g, 99%) as a white solid. [M+H]+ 232.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([NH:39][NH2:40])=[O:38])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[O:38][C:41](=[O:42])[NH:40][N:39]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4n[nH]c(=O)o4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide (4.5 g, 8.03 mmol) and 1,1′-carbonyldiimidazole (1.43 g, 8.84 mmol) dissolved in acetonitrile (53.6 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one. MS ESI calc'd. for C31H32ClN7O3 [M+H]+ 586. found 586. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.79 (d, J=8.3, 2H), 8.27 (s, 1H), 7.87 (s, 1H), 7.42 (t, J=10.0, 2H), 7.25 (t, J=7.2, 2H), 7.22-7.17 (m, 1H), 4.76 (s, 1H), 4.05-3.81 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.47 (m, 2H), 3.27 (s, 1H), 1.37 (t, J=13.0, 2H), 1.03 (broad, 1H), 0.83 (broad, 1H), 0.68 (d, J=6.2, 4H), 0.64-0.52 (m, 2H), 0.51-0.27 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=2)[C:31](O)=[O:32])[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[C:30]([C:31]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:17]([CH2:16][O:15][C:14]4[C:4]5[C:3]([NH2:2])=[N:8][S:7](=[O:9])(=[O:10])[NH:6][C:5]=5[CH:11]=[CH:12][CH:13]=4)[CH2:18]3)=[O:32])[CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)c4ccnc(-n5ccnc5)c4)C3)c21

Procedure:
Prepared as in Example 2 from (S)-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (Example 2a) and 2-(1H-imidazol-1-yl)isonicotinic acid (Example 52a) (42% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 1.42-1.60 (m, 2H), 1.71 (m, 1H), 1.93 (m, 1H), 2.22 (m, 1H), 3.11 (m, 1H), 3.34-3.75 (m, 1H), 3.92-4.42 (m, 2H), 6.63 (m, 1H), 6.74 (br s, 1H), 7.11 (s, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52-8.28 (br s, 2H), 7.76 (m, 1H), 7.93 (m, 1H), 8.52 (m, 2H), 10.71 (br s, 1H). MS 482 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH3:19]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (10.0 g) in DMF (120 ml) were added potassium carbonate (15.8 g) and 1-bromopropane (12.1 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, which was extracted with ethyl acetate and washed with 1N sodium hydroxide solution twice, with water three times and with saturated brine once. After dried with magnesium sulfate, the solvent was evaporated under reduced pressure to give 3-propoxybenzaldehyde (13.4 g) as colorless liquid.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:22][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 2.00 g (20 mmol) of cyclohexanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water, and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.30 g (yield: 92%) of 6-cyclohexyloxynicotinic acid.