Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl.[CH2:8]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.COCCOC>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: NCCCBr
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)NCCCBr)cc1

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.9 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution was heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([NH2:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:39]([NH:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCN
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 10.0 g (16.5 mmole) of 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)], 9.5 mL (7.14 g, 8.2 mmole) of n-pentylamine, 2.8 mL (2.03 g, 20 mmole) of triethylamine, and 100 mL of dry methylene chloride was stirred under N2 at room temperature overnight. Next, the mixture was shaken with 100 mL of 0.25M citric acid (aqueous). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The viscous oil was flash chromatographed on silica gel (elution initially with 1:1 hexane-EtOAc and then with a larger volume of EtOAc alone) to yield 4.57 g (49%) of the title compound as a very viscous oil, homogeneous by TLC (EtOAc); FAB-MS m/e 563 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[O:6][CH2:5]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC1CO1
Reactant: NCCCCCCN
Product: CC(C)CC(O)CNCCCCCCNCC(O)CC(C)C

Procedure:
Condensation of 4-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-4-methylpentylamine] (I: R= (CH3)2CHCH2, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[S:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:15]2[CH2:16][CH2:17][S:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCSCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCSCC1
Temperature: 80 °C
Yield: 50.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol), tetrahydro-2H-thiopyran-4-amine (0.304 g, 2.59 mmol) and DIEA (0.91 mL, 5.19 mmol) were taken up in ethanol (2.0 mL) and heated to 80° C. for 18 h in a sealed tube. The reaction solution was chilled to form a precipitate. The precipitate was collected by vacuum filtration to give the title compound (0.360 g) LCMS m/z=274.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.70-1.85 (m, 2H), 2.20-2.35 (m, 2H), 2.60-2.90 (m, 4H), 3.90-4.10 (m, 1H), 5.84 (d, J=10.0 Hz, 1H), 8.24 (d, J=9.3 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([I:15])=[CH:9][CH:8]=3.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([I:1])=[CH:3][CH:4]=3
Reactant: OCCCCCCCCCCCBr
Reactant: Ic1ccc2[nH]c3ccc(I)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCCCCCCn1c2ccc(I)cc2c2cc(I)ccc21
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 3,6-diiodocarbazole (10.0 g, 23.87 mmol) and 11-bromo-1-undecanol (7.0 g, 27.87 mmol) in DMF (100.0 ml) was added K2CO3 (32.0 g, 231.33 mmol). The reaction was carried out at room temperature for 24 h. Water (300 ml) was added. The precipitate was filtered. The crude product was purified by silica gel column using Hexane/ethyl acetate (7:3) as solvent. 12.4 g (87.9%) of pure product as white solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([NH:11][CH2:10][CH2:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:14]2
Reactant: O=C1CN2CCC1CC2
Reactant: NCCNc1cccc(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(NCCNC2CN3CCC2CC3)c1
Yield: 40.3 %

Procedure:
To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (1 g; 0.00586 moles) in 25 ml of anhydrous methanol kept under nitrogen atmosphere, 3-quinuclidinone hydrochloride (1.01 g, 0.00627 moles) is added. The pH is adjusted to pH 6 by addition of glacial acetic acid. Sodium cyanoborohydride (0.74 g; 0.0117 moles) is added in two portions. The reaction mixture is refluxed for 10 hours, cooled and then filtered. After evaporation to dryness the residue is taken up with water, basified with 20% sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by silica gel flash-chromatography (methylene chloride-methanol30% ammonium hydroxide, 1.50:50:5 as eluant) to give the desired product as a clear oil (0.66 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@H:11]1[CH2:15][NH:14][CH2:13][C@@:12]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:9]=[CH2:10].[CH2:31]([N:38]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:40](O)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:8]([C@H:11]1[CH2:15][N:14]([C:40](=[O:41])[CH2:39][N:38]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH2:13][C@@:12]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:9]=[CH2:10]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CN(C(=O)CN(Cc2ccccc2)C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A stirred mixture of the crude racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate trifluoroacetate (Step 1, ˜1 mmol) and N-benzyl-N-(tert-butoxycarbonyl)glycine (337 mg, 1.27 mmol) in methylene chloride (9 mL) was treated with Et3N (0.495 mL, 3.55 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 502 mg, 1.32 mmol), and the resulting mixture was stirred at room temperature and monitored by HPLC. At 1 h, the reaction was diluted with methylene chloride (20 mL), washed with water (20 mL), 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g column, 15-30% ethyl acetate in hexanes) gave 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azido-1-[N-benzyl-N-(tert-butoxycarbonyl)glycyl]pyrrolidine-3-carboxylate (365 mg, 64%) as an amber gum which was used as is in the next step. LC-MS ESI+MS found for C30H35N5O6 m/z 562.3 (M+H), 584.3 (M+Na), 1H NMR (CDCl3, 400 MHz) δ 7.92 (m, 2 H), 7.66 (m, 1 H), 7.53 (m, 2 H), 7.30 (m, 5 H), 5.75 (m, 1 H), 5.52 (m, 2 H), 5.12 (m, 2 H), 4.58 (m, 2 H), 4.22-3.42 (m, 6 H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.12 (m, 1 H), 1.48 (s, 9 H).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH:21]C(=O)[O-])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH2:21])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To an ice-cooled solution of tert-butyl (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-ylcarbamate (prepared according to the method described in example 1) (227 mg, 0.587 mmol) in CH2Cl2 (5 mL) under argon atmosphere was added TFA (1.5 mL) dropwise. The reaction solution was allowed to reach r.t. and stirred overnight. The mixture was cooled down and 0.5 N NaOH solution was added until basic pH. The product was extracted with CH2Cl2 three times. The combined organic fractions were washed with sat. NaCl solution, dried over Na2SO4, and the solvent removed under reduced pressure after filtration giving (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-amine (145 mg, 86%) as orange viscous solid. The product was used without further purification.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][C:15]([NH2:17])=[S:16])=[CH:11][CH:10]=2)[O:8]CCO1.C([CH:20](Br)[C:21](=O)[C:22]([O-:24])=[O:23])C.[CH2:27](O)[CH3:28]>>[CH2:27]([O:24][C:22]([C:21]1[N:17]=[C:15]([CH2:14][C:12]2[S:13][C:9]([C:4](=[O:8])[CH3:3])=[CH:10][CH:11]=2)[S:16][CH:20]=1)=[O:23])[CH3:28]
Reactant: CCO
Reactant: CC1(c2ccc(CC(N)=S)s2)OCCO1
Reactant: CCC(Br)C(=O)C(=O)[O-]
Agent: N#N
Product: CCOC(=O)c1csc(Cc2ccc(C(C)=O)s2)n1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-thioacetamide (2.88 g, 11.83 mmol) and ethylbromopyruvate (1.74 mL, 11.83 mmol) in ethanol (34.0 mL) was stirred for 16 h at reflux. The solvent was removed under reduced pressure and the residue was dissolved in EA (150 mL) and washed with 7% aq. NaHCO3 (100 mL). The org. phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.24. LC-MS-conditions 02: tR=0.93 min, [M+H]+=296.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:28]([C:25]3([C:23]4[CH:22]=[CH:21][C:20]5[O:16][CH2:17][O:18][C:19]=5[CH:24]=4)[CH2:27][CH2:26]3)=[O:29])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1Cc1cnc(N)s1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ncccc1Cc1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1
Temperature: 78 °C
Reaction time: 12 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (221 mg, 1.00 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (206 g, 1.00 mmol) were dissolved in acetonitrile (5 mL) containing triethylamine (0.421 mL, 3.00 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 760 mg, 2.0 mmol) was added and the solution was allowed to stir at 78° C. for 12 hours. An aliquot of the crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 409.1. found; 410.3 (M+1)+ Retention time 3.23 minutes.
Reaction SMILES: Br.[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][C:11]=3[C:20](=[O:22])[O:21][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:33][CH3:34])(=O)=O.[CH3:38][C:39](C)=O>>[CH2:33]([O:2][C:3]1[C:8]([O:9][CH2:38][CH3:39])=[CH:7][C:6]2[C:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][C:11]=3[C:20](=[O:22])[O:21][C:5]=2[CH:4]=1)[CH3:34]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)=O
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(O)c(O)cc23)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CC(C)=O)C3

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dihydroxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrobromide (108 g, 0.29 moles), potassium carbonate (155 g, 1.12 moles), and diethyl sulfate (118 g, 0.76 moles) in 2.5 l of acetone is stirred at reflux for 21 hours. Additional diethyl sulfate (59 g, 0.38 moles) is added, and the mixture is heated for an additional 30 hours. The cooled mixture is filtered, and the filter cake is digested twice in hot acetone (500 ml) and refiltered. The combined filtrates are evaporated, and the residue is distributed between dichloromethane (1500 ml) and water (750 ml). The organic layer is separated, washed 4 times with 2.5% aqueous sodium hydroxide (750 ml), dried over sodium sulfate, and evaporated. The residue is recrystallized as the free base from methanol and washed with cold hexane to yield the final product (36.3 g), mp 146°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:30])[C:17]3[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=3[F:18])[C:11](=[O:20])[N:10]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=2[F:29])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:31][O:32][C:33]([NH:35][C:36](=NC(OC)=O)SC)=[O:34].[OH-].[Na+]>C(O)(=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:35][C:36]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3([OH:30])[C:17]4[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=4[F:18])[C:11](=[O:20])[N:10]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=3[F:29])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc(N)c(N)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc3[nH]c(NC(=O)OC)nc3c2)c1F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(3,4-diaminophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.15 g, 2.80 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2.80 mmol) was heated to 80° C. for 30 minutes in glacial acetic acid (15.0 mL). The reaction mixture was cooled to room temperature and it was pored into ice water. The pH was adjusted to 8 by the addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (350 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and evaporation resulted in a crude product. It was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was freeze-dried from a mixture of acetonitrile-water (35.0 mL) to give methyl{5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate (1.15 g, 83% yield). 1H NMR (400 MHz, CD3OD): 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 4H), 7.31 (t, J=7.2 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 1H); MS (EI) for C25H15F3N4O4: 493 (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20].NC(N)=N>>[N+:19]([O-:22])([O-:21])=[O:20].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]([NH2:18])=[NH2+:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: N#CN
Reactant: Nc1ccc(OCCn2ccnn2)cc1
Reactant: O=[N+]([O-])O
Agent: N=C(N)N
Product: NC(=[NH2+])Nc1ccc(OCCn2ccnn2)cc1
Product: O=[N+]([O-])[O-]

Procedure:
The title compound was prepared from 4-[2-(1,2,3-triazol-1-yl)ethoxy]aniline (4.91 g, 24.07 mmol), cyanamide (1.56 g, 40.97 mmol) and concentrated HNO3 (1.58 mL, 26.47 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (4.7 g) as an off-white solid, m.p.>250°. δH (d6DMSO) 9.33 (1H, s), 8.20 (1H, s), 7.74 (1H, s), 7.17-7.14 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H, t, J 4.95 Hz) and 4.41 (2H, t, J 4.95 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.ClCCCC.N1C=CC=NC=1>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:11]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:17])=[O:21])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Solvent: c1cncnc1
Solvent: CCCCCl
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a suspension of 1.2 g of 2-amino-4,6-dimethylpyrimidine in 25 ml of acetonitrile was added 2.6 g of 1,1'-biphenyl-2-sulfonyl isocyanate with stirring at ambient temperature. After stirring for 2 hours, the mixture was filtered and the filtrate concentrated in vacuum. The residue thus obtained, after trituration with chlorobutane, melted at 78° with gas evolution. It showed peaks in the nuclear magnetic resonance spectrum (60 MHz) at δ 2.2, (singlet, CH3); δ 6.56, (singlet, CH of pyrimidine) and at δ 6.8-7.9, (multiplet, phenyl hydrogens) in a ratio of 6:1:9, consistent with the desired structure.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1.[NH2:35][CH2:36][CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH:19]=[C:20]([NH:35][CH2:36][CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1
Reactant: NCC(O)C(F)(F)F
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(NCC(O)C(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 96 mg (200 μmol) N-cyclopropyl-4-[6-(3-fluorophenoxy)-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide which was prepared according to intermediate example 486a in 2 mL NMP is added 77.5 mg (0.6 mmol) 3-amino-1,1,1-trifluoropropan-2-ol and 77.5 mg (0.6 mmol) DIPEA and the mixture is heated at 160° C. for 30 min in a microwave oven. After working up and purification 10.5 mg (9%) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@@H:40]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in the starting materials used in Example 22; 4.0 g, 12.5 mmol) was mixed with tert-butyl (3S)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (4.7 g, 12.6 mmol) and cesium fluoride (5.7 g, 7.5 mmol). Dry N,N-dimethylformamide (60 ml) was then added and the mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, 50% aqueous brine then brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the expected product were combined and evaporated to give 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline as a dry foam (2.35 g, 38%); 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 2.10-2.30 (m, 2H); 3.35-3.50 (m, 3H); 3.64-3.71 (m, 1H); 3.92 (s, 3H); 5.12 (m, 1H); 7.21 (s, 1H); 7.23-7.27 (m, 1H); 7.44-7.55 (m, 2H); 7.80 (s, 1H); 8.37 (s, 1H); 9.61 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].[CH:33]([O-:35])=[O:34].[NH4+]>[Pd].CO>[CH:33]([OH:35])=[O:34].[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: O=CO
Temperature: 80 °C
Yield: 75.4 %

Procedure:
Palladium on activated carbon (0.4 g, 10% w/w) was added to a suspension of (R)-5-(2-azido-1-(tert-butyldimethylsilyloxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one (2.05 g, 4.60 mmol) and ammonium formate (2.87 g, 63 mmol) in methanol (50 mL). The reaction mixture was heated at 80° C. for 1 hour and then filtered through celite, washing with water. The reaction mixture was concentrated under reduced pressure. The resultant solid was washed with water, triturated with ethyl acetate and collected by filtration to afford the title compound (1.32 g, 86%).