Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([O:27]CCCC)(=[O:26])=[O:25])[CH2:21]1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S-])#N.[K+:35]>COCCOC.O>[CH2:13]([O:12][CH2:11][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([O-:27])(=[O:26])=[O:25])[CH2:21]1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+:35]
Reactant: CCCCOS(=O)(=O)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Agent: N#C[S-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=S(=O)([O-])C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Yield: 74.2 %

Procedure:
Using the same reaction conditions, procedure and work up as described Intermediate I-25b (below), butyl 3-(1,3-bis(benzyloxy)propan-2-yl)cyclobutane-1-sulfonate (0.1 g, 0.22 mmol) was reacted with KSCN (24 mg, 0.24 mmol) and DME-water mixture (2 mL) to afford 0.07 g of the product (83% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:12][C@@:11]3([CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][N:20]4[C:24]5[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)([CH3:18])[CH2:13]3)[O:10][C:9]2=[O:31])=CC=1>C(O)(C(F)(F)F)=O>[CH3:18][C@:14]1([CH2:19][N:20]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[CH2:15][CH2:16][CH2:17][C@:11]2([O:10][C:9](=[O:31])[NH:8][CH2:12]2)[CH2:13]1
Reactant: COc1ccc(CN2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CNC(=O)O2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A yellow solution of 1-(((5S,7S)-3-(4-methoxybenzyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.012 g, 4.53 mmol) in TFA (20.12 ml) was heated at 70° C. The reaction mixture turned dark brown overnight. Additional TFA (5 mL) was then added to the reaction mixture. After 21 h, additional TFA (5 mL) was added. After 23 h, reaction was completed as indicated by LCMS. The reaction mixture was then cooled to RT and concentrated. 2N NaOH (40 mL) and DCM (50 mL) were added to the mixture (aqueous layer was pH 13). The layers were separated and the aqueous layer was extracted with DCM (2×25 mL). Combined organic layers were dried over Na2SO4, filtered, and concentrated. The compound was loaded onto florisil and purified using silica gel chromatography CISCO): 1-5% MeOH/DCM (30 min), 5% (15 min), 40 g silica. Product began eluting at 22 minutes. The product was dried under high vacuum at 40° C. overnight to yield 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as a yellow solid (729 mg, 47.2% yield). MS (m/z) 325 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].ClC1N=C(OC)N=C(OC)N=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:33]([O:34][CH3:35])[CH3:32])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CNOC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
2-Bromo-isonicotinic acid (0.5 g, 2.47 mmol) was dissolved in dry THF (10 mL). 2-Chloro-4,6-dimethoxy[1,3,5]triazine (0.77 g, 4.4 mmol) and diisopropylethylamine (0.96 g, 0.74 mmol) were added and the solution was stirred for 1 hour after which N,O-dimethyl hydroxylamine hydrochloride (0.241 g, 2.47 mmol) was added. The mixture was stirred for a further 16 hours at room temperature and then diluted with water (15 mL). The aqueous mixture was then extracted with EtOAc (3×10 mL). The combined organics were washed successively with a saturated aqueous Na2CO3, 1N aqueous HCl and then brine. The organic phase was dried (Na2SO4) and then evaporated to dryness. Purification by SiO2 chromatography (eluting with EtOAc/hexane; 2:1) gave a product which was then suspended in Et2O. The insoluble material was removed by filtration and the filtrate was evaporated in vacuo to give 2-bromo-N-methoxy-N-methyl-isonicotinamide (0.342 g, 56%). MS(ESI) m/z 244.9 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C=Nc1ccc(Br)cc1
Product: O=C(Nc1ccc(Br)cc1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 76.6 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 1, was reacted with 4-bromophenylisocyanate (7.6 mmol) as described in Method A to obtain 2.3 g of the title product as a solid. 1H NMR (CD3SOCD3): δ9.35 (s, 1 H), 7.87 (d, J =8 Hz, 1 H), 7.82 (s, 1 H), 7.78 (d, J =8 Hz, 1 H), 7.58 (dd, J =8, 8 Hz, 1 H), 7.46 (d, J =9 Hz, 2 H), 7.44 (dd, J =8, 8 Hz, 1 H), 7.38 (d, J =9 Hz, 2 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:19](=O)[CH:18]([CH3:21])[CH2:17][C:13]=3[S:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[CH:19]=[C:18]([CH3:21])[CH2:17][C:13]=3[S:14][C:15]=2[CH3:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc2c(c1-c1ccc(C(C)(C)C)cc1)C(=O)C(C)C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC1=Cc2c(sc(C)c2-c2ccc(C(C)(C)C)cc2)C1
Reaction time: 2.5 h

Procedure:
To a solution containing 12.9 g (43 mmol) 3-(4-tert-Butyl-phenyl)-2,5-dimethyl-5,6-dihydro-cyclopenta[b]thiophen-4-one dissolved in 100 ml diethyl ether was added 22 mmol lithium aluminum hydride (1M in diethyl ether, 22 ml added) at room temperature. The reaction mixture was stirred for 2.5 h, then a saturated solution of ammonium chloride was slowly added (3 ml). The solids were filtered and the organics were collected with 30% dichloromethane/70% hexane, washed with water, dried over magnesium sulfate, filtered, then solvents removed in vacuo. The partially dehydrated product (12.3 g of a brown oil), was dissolved in 50 ml toluene and a catalytic amount of para-toluenesulfonic acid monohydride (0.25 g) was added, The flask contents were refluxed for 1 h, then stirred at room temperature overnight. The organic fraction was washed with water, dried over magnesium sulfate, filtered, then solvents removed in vacuo. Yield: 10.1 g (77.4%) dark brown oil. Olefin: (2 isomers); 1H NMR (CD2Cl2): δ 7.1–7.7 (m, 4H), 6.4–6.5 (2s, 1H), 3.18, 3.3 (2s, 2H), 2.4–2.6 (m, 3H), 2.18 (m, 3H), 1.4 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]3[CH:19]=[CH:20][N:21]=[C:15]3[CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1>[N:21]1[CH:20]=[CH:19][N:16]2[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:30]([C:25]4[C:24]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:32])=[O:31])=[CH:3][CH:4]=3)=[O:10])=[CH:14][C:15]=12
Reactant: Nc1ccc(NC(=O)NCc2ccn3ccnc3c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1ccn2ccnc2c1)Nc1ccc(NS(=O)(=O)c2ccccc2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
In a 4 mL vial was mixed 1-(4-aminophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea (50 mg, 0.178 mmol) in anhydrous tetrahydrofuran (2 mL). To this mixture at room temperature was added 60% sodium hydride (24.88 mg, 0.622 mmol). The reaction was stirred about 30 minutes and biphenyl-2-sulfonyl chloride (53.9 mg, 0.213 mmol) was added. The reaction mixture stirred overnight at room temperature and was quenched with saturated ammonium chloride and water. The aqueous solution was extracted with dichloromethane and 10% methanol/dichloromethane. The organic layers were combined, concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (bs, 1H), 8.56 (s, 1H), 8.47 (dd, J=6.9, 0.9 Hz, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.87 (dd, J=1.2, 0.6 Hz, 1H), 7.62 (m, 1H), 7.54 (m, 1H), 7.51 (m, 1H), 7.38 (m, 4H), 7.30-7.20 (m, 5H), 6.82 (m, 3H), 6.66 (t, J=6.0 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H); (ESI(+)) m/e 498 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=O)[CH2:22][CH2:21]4)=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].Cl.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:32][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:20]2([NH:19][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:18])[CH2:22][CH2:21]2)[CH:24]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Reaction time: 4 h

Procedure:
To a solution of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid (0.200 g, 0.480 mmol), Gly-OMe.HCl (68.1 mg, 0.543 mmol) and N,N-diisopropylethylamine (426 μL, 2.40 mmol) in DMF (4.5 mL) is added TBTU (192 mg, 0.600 mmol). After 4 hours, the mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate (100 mL) and washed with 2N sodium hydroxide (3×50 mL), saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL). The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to give a foam, which is triturated with ether (3 mL), filtered, washed with cold ether (3×3 mL) and air dried to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1.F[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>N1C=CC=CC=1>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)=[CH:28][CH:27]=1
Reactant: Fc1nc2ccccc2s1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture constituted by 1-4 (150 mg, 0.4 mmole) and 2-fluorobenzothiazole (75 mg; 0.5 mmole) in 3 ml of pyridine is agitated at ambient temperature then heated under reflux for minutes, followed by evaporating under reduced pressure and purifying by chromatography eluting with an AcOEt/CH2Cl2 mixture 50/50 in order to obtain 90 mg of the expected 2-1.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:29]([C:34]([OH:36])=O)=[CH:30][CH:31]=[CH:32][CH:33]=1>O>[Cl:20][C:21]1[C:22]2[C:28]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34](=[O:36])[C:23]=2[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)c1ccccc1-c1ccc(F)cc1Cl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C1c2ccccc2-c2c(Cl)cc(F)cc21
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a mixture of phosphorus pentoxide (133 g) and methanesulfonic acid (1300 ml) was added 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid (132.9 g), and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was ice-cooled, water (1300 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was washed with water (300 ml). The solid was mixed with 50 v/v % ethanol-water (1300 ml), and the slurry was stirred at room temperature for 1.5 hr, and filtered. The obtained solid was washed with 50 v/v % ethanol-water (200 ml), air-dried for 3 hr, and dried under reduced pressure at 60° C. to give the title compound (121.6 g, 99%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:5]2[CH:4]=[C:3]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)-N-3-pyridinylbenzamide (may be prepared as described in Example 15; 95 mg, 0.19 mmol) in 1,2-dimethoxyethane (5 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47.4 mg, 0.23 mmol), Pd(Ph3P)4 (13.16 mg, 0.01 mmol) and sodium carbonate (0.38 ml, 0.38 mmol). The mixture was heated at 120° C. in the microwave for 35 minutes, cooled and the solvent removed in vacuo to give a solid. Purification by MDAP yielded the title compound as a colourless gum. 36 mg.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[O:16])[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(NC(=O)C3CNC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-(4-(1-(benzyloxycarbonyl)azetidine-3-carboxamido)phenylsulfonyl)piperidine-1-carboxylate (7.94 g, 14.24 mmol) and ethanol (160 ml) were added to 20% Pd(OH)2/C, wet (1.5 g, 1.089 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound.
Reaction SMILES: [NH:1]([CH:6]([CH3:11])C(NN)=O)[NH:2][C:3]([NH2:5])=[O:4]>O.CN(C)C=O.[N-]=C=O>[NH:1]([CH2:6][CH2:11][C:3]([NH:2][NH2:1])=[O:4])[NH:2][C:3]([NH2:5])=[O:4]
Reactant: CC(NNC(N)=O)C(=O)NN
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)CCNNC(N)=O

Procedure:
11.8 parts of semicarbazido-propionic acid hydrazide were dissolved in 23.0 parts of water and 580 parts of dimethylformamide, and 268.75 parts of isocyanate prepolymer solution (a) were added. The clear, colourless elastomeric solution was pigmented with 4% TiO2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH2:19]1COCC1.C[Mg]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH2:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2oc3ncc(Br)cc3c(=O)c2c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: C=C1c2cc(OC)ccc2Oc2ncc(Br)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-7-methoxy-5H-chromeno[2,3-b]pyridin-5-one (4.50 g, 14.7 mmol) in THF (294 ml, 14.7 mmol) at 5° C. was added methylmagnesium bromide (1 M in butyl ether) (36.8 ml, 36.8 mmol). The reaction was removed from the ice bath and stirred for an additional 1 hour. TLC showed complete conversion to a lower Rf material. The reaction mixture was quenched with saturated ammonium chloride (250 mL) and to it DCM (100 mL) was added. The mixture was stirred vigorously for 30 minutes before being poured into a separatory funnel containing 300 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM 2×100 mL. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. TLC revealed tertiary alcohol and no olefin. The organics were concentrated under reduced pressure at 60° C. Flask was maintained at 60° C. on the rotovap for 1 hour at which point TLC and NMR show clean conversion to 3-bromo-7-methoxy-5-methylene-5H-chromeno[2,3-b]pyridine. MS m/z=304.2 [M+H]+. Calc'd for C14H11BrNO2: 304.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[N:17]=[C:16]([CH3:18])[N:15]=[C:14](O)[CH:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>ClCCl>[Cl:22][C:14]1[CH:13]=[C:12]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:11][CH2:10][CH2:9]2)[N:17]=[C:16]([CH3:18])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)cc(C2(c3ccc(Cl)cc3)CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCC2)n1
Temperature: 20 °C
Yield: 85 %

Procedure:
To 6-[1-(4-chlorophenyl)cyclobutyl]-2-methylpyrimidin-4-ol (1.00 g, 3.65 mmol) was added phosphorous oxychloride (10 mL) and the mixture was refluxed for 1.5 h. After cooling to 20° C., the reaction mixture was poured into ice/water (55 mL). After the addition of dichloromethane, the mixture was neutralized with 32% aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with 0.1 N sodium hydroxide solution and with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/methanol (95:5 v/v) as eluent to afford the title compound (0.91 g, 85%) as an off-white solid. Mp 96-98° C.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(N)o1

Procedure:
A mixture of 53.3 g. of ethyl 5-nitro-2-furancarboxylate, 5 g. of 10% palladium on carbon, and 250 ml. of absolute ethanol is shaken in an atmosphere of hydrogen until no more hydrogen is taken up. The catalyst is filtered and the filtrate evaporated. The thick oily residue is dissolved in a small amount of methylene chloride and the solution is filtered through Magnesol. The solvent is evaporated to yield the product.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[CH2:4][CH2:5][N:6]1[C:29](=[O:30])[C:10]2[CH:11]=[C:12]([N+:26]([O-])=O)[CH:13]=[C:14]3[O:15][C:16]4[CH:17]=[C:18]5[CH:25]=[CH:24][CH:23]=[CH:22][C:19]5=[CH:20][C:21]=4[N:8]([C:9]=23)[C:7]1=[O:31].[H][H]>C(O)(=O)C.[C].[Pd]>[ClH:1].[ClH:1].[NH2:26][C:12]1[CH:13]=[C:14]2[C:9]3=[C:10]([C:29](=[O:30])[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:32])[C:7](=[O:31])[N:8]3[C:21]3[CH:20]=[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]4=[CH:17][C:16]=3[O:15]2)[CH:11]=1
Reactant: CN(C)CCn1c(=O)c2cc([N+](=O)[O-])cc3c2n(c1=O)-c1cc2ccccc2cc1O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCn1c(=O)c2cc(N)cc3c2n(c1=O)-c1cc2ccccc2cc1O3
Temperature: 25 °C

Procedure:
268 mg (0.641 mmol) of the free base of the compound of Example 27 was dissolved in acetic acid (10 ml) and 10% palladium-carbon was added thereto. Then catalytic reduction was effected at room temperature in a hydrogen atmosphere. After filtering off the palladium-carbon through celite, the filtrate was concentrated. Next, water and a saturated aqueous solution of sodium hydrogencarbonate were added thereto and the obtained mixture was stirred at room temperature. The precipitate was recovered by filtration, washed with water and suspended in methanol. After adding conc. hydrochloric acid thereto, the obtained mixture was stirred at room temperature. Thus it turned into a homogeneous solution and then a precipitate was formed. The precipitate was recovered by filtration to thereby give 179 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[O:37][N:36]=[C:35]([CH3:38])[N:34]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[I-].C1COCC1.C(OCC)(=O)C>[CH3:38][C:35]1[N:34]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:21][CH2:22][N:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:12][CH2:13]3)[C:19]2=[O:20])[O:37][N:36]=1
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: Cc1noc(-c2ccccc2CBr)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccccc2CN2CCCC3(CCN(c4cnc5ccccc5n4)CC3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a suspension of 9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (41 mg, 0.14 mmol) and TBAI (2.6 mg, 6.9 μmol) in THF (0.6 ml) was added sodium hydride (7.0 mg, 95%, 2.8 mmol) at 0° C. The yellow suspension was stirred for 20 min at 0° C. under argon. A solution of 5-(2-(bromomethyl)phenyl)-3-methyl-1,2,4-oxadiazole in dry THF (0.4 ml) was added and stirring was continued for 2 h at rt. To the reaction mixture was added water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phases were washed with water and brine, combined and dried over sodium sulfate, filtered and evaporated to give 64 mg (98%) of a pale brown oil. [1H NMR (600 MHz, DMSO-d6) ♀ ppm 8.84 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.55-7.62 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.34-7.41 (m, 1H), 7.27 (d, J=7.7 Hz, 1H), 4.91 (s, 2H), 4.23-4.34 (m, 2H), 3.46 (t, J=11.1 Hz, 2H), 3.26-3.32 (m, 2H), 2.44 (s, 3H), 2.04-2.12 (m, 2H), 1.93-2.01 (m, 2H), 1.83-1.92 (m, 2H), 1.66 (d, J=13.5 Hz, 2H); LCMS RtD=2.63 min, [M+H]+=469.2].
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[C:14]([CH:19]3[CH2:21][CH2:20]3)[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:38][CH3:39])[CH:11]=3)[N:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH2:20]2)=[CH:24][CH:25]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(C3CC3)cnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(C3CC3)cnc2cc1O

Procedure:
A mixture of N-[4-(7-benzyloxy-3-cyclopropyl-6-methoxy-quinolin-4-yloxy)-phenyl]-benzamide (50 mg, 0.097 mmol) in TFA (750 μl) and thioanisole (90 μl) was refluxed for 1 hour, cooled and concentrated under high vacuum to use crude in the next stage.