Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Temperature: 65 °C

Procedure:
KOH (2.12 g, 37.8 mmole), indole (1.0 g, 8.54 mmole) and 1-benzyl-3-piperidone hydrochloride (4.82 g, 21.34 mmole) were suspended in methanol (20 ml) and heated for 8 hours at 65° C. under argon. Water (40 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The methanol was distilled off and the aqueous phase was extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. 3-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-indole was purified by chromatography with cyclohexane/EE (1:1). The product was obtained as a yellow solid in a yield of 860 mg (35%) and an m.p. of 105°-107° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][C:13]2=[O:29])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.Cl[NH:32][CH:33]=O.[N:35]1C=CC=CC=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:21]2[N:20]=[C:19]([CH2:18][CH:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:9]4[CH:10]=[C:3]5[C:4]([C:5]([NH2:35])=[N:6][C:33]([NH2:32])=[N:2]5)=[CH:7][CH:8]=4)[C:13](=[O:29])[CH2:14]3)[NH:23][C:22]=2[CH:24]=1
Reactant: c1ccncc1
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Reactant: O=CNCl
Agent: Cl
Product: Nc1nc(N)c2ccc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)cc2n1
Temperature: 200 °C
Yield: 45 %

Procedure:
2-Amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (70 mg, 0.15 mmol), EXAMPLE 814, Part E, pyridine (1.0 mL) and freshly made chloroformamide hydrochloride (150 mg, 1.33 mmol) are placed in a sealed tube and heated to 200° C. The resulting mixture is heated for twenty four hours. The crude reaction mixture is directly purified by reverse phase HPLC (0-50% ACN/H2O). The product (53 mg, 45% yield) is isolated as a tanish solid. C22H22ClN7O MS m/z: 436,438. Anal. calcd. for C22H22ClN7O: C, 43.23; H, 3.24; N, 12.60. Found: C, 43.16; H, 3.44; N, 13.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1(O)[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH:10]=1
Reactant: COc1ccccc1C1(O)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1=CCC(=O)CC1
Temperature: 80 °C

Procedure:
To a solution of 8-(2-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (100 mg, 0.379 mmol) in 10 mL THF was added HCl (1.4 mL 6M, 8.4 mmol). The solution was heated to 80° C. for 45 min, then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (dichloromethane/3% methanol as eluent) to give 4-(2-Methoxy-phenyl)-cyclohex-3-enone
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH2:13][F:14])[CH2:11][O:10][C:9]2=[O:15])[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C@@H:29]([NH2:31])[CH3:30])=[N:26][CH:25]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][C:27]([C@@H:29]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH2:13][F:14])[CH2:11][O:10][C:9]4=[O:15])[C:5]([F:16])=[CH:4][N:3]=3)[CH3:30])=[N:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: O=C1OC[C@H](CF)N1c1nc(F)ncc1F
Reactant: C[C@H](N)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2CF)n1)c1ncc(-c2ccc(Cl)cc2)o1
Temperature: 120 °C
Yield: 86.4 %

Procedure:
(R)-3-(2,5-difluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one (105 mg, 0.449 mmol), (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine (100 mg, 0.449 mmol), and DIPEA (157 ul, 0.898 mmol) were dissolved in DMSO (1 mL) and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, and concentrated in vacuo. Column chromatography (5-50% EtOAc/DCM) gave the desired product (169 mg) as a white foam. 1H NMR (400 MHz, CDCl3) b 8.26 (d, J=2.8 Hz, 1H), 7.59-7.50 (m, 2H), 7.45-7.36 (m, 2H), 7.25 (s, 1H), 5.66 (d, J=7.6 Hz, 1H), 5.21 (br s, 1H), 4.86 (ddddd, J=20.0, 8.6, 7.0, 4.3, 2.8 Hz, 1H), 4.66-4.44 (m, 3H), 4.41 (br s, 1H), 1.71 (d, J=7.0 Hz, 3H). HRMS-Acidic. LC-UV/ESI-MS data was recorded on an Acquity LCTp Tof—Rs(FWHM) >12000 Accuracy <5 ppm. Column: Acquity BEHC18 1.7 μm 2.1×50 mm-50° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].Cl.[CH3:13][NH:14][CH:15]1[CH2:17][CH2:16]1.Cl.Cl.C[Si](C)(C)CCOC[N:26]1[C:30]2[N:31]=[CH:32][N:33]=[C:34]([C:35]3[CH:36]=[N:37][N:38]([C:40]4([CH2:44][C:45]#[N:46])[CH2:43][NH:42][CH2:41]4)[CH:39]=3)[C:29]=2[CH:28]=[CH:27]1>>[C:45]([CH2:44][C:40]1([N:38]2[CH2:39][CH:35]([C:34]3[C:29]4[CH:28]=[CH:27][NH:26][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:36]=[N:37]2)[CH2:43][N:42]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH:15]3[CH2:17][CH2:16]3)[CH3:13])=[O:8])=[CH:4][C:3]=2[F:11])[CH2:41]1)#[N:46]
Reactant: CNC1CC1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Product: CN(C(=O)c1ccc(N2CC(CC#N)(N3CC(c4ncnc5[nH]ccc45)C=N3)C2)c(F)c1)C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 4-bromo-3-fluorobenzoic acid, N-methylcyclopropanamine hydrochloride (J&W PharmLab: Cat. 420-0433S) and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=471.2. 1H NMR (400 MHz, DMSO-D6): δ 12.83 (s, 1H), 9.17 (s, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.33 (m, 3H), 6.71 (t, J=9.0 Hz, 1H), 4.66 (d, J=8.0 Hz, 2H), 4.41 (d, J=8.0 Hz, 2H), 3.79 (s, 2H), 2.97 (m, 1H), 2.93 (s, 3H), 0.59 (m, 2H), 0.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1CC1)c1ccc(F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=333.1, tR (minutes, Method F)=2.43
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([C:22]=1[I:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=[O:13].CCN(CC)CC>C(Cl)Cl.CS(C)=O>[O:7]=[CH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([C:22]=1[I:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=[O:13]
Reactant: O=C(NCCCO)c1[nH]c2ccc(F)cc2c1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (3.68 g, 30 mmol) in anhydrous CH2Cl2 (50 mL) at −40° C. is added DMSO (4.52 g, 57.9 mmol) drop-wise. The mixture is stirred at this temperature for 5 minutes. 5-Fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide, prepared as in reference 12, (6.99 g, 19.3 mmol) is dissolved in CH2Cl2 (800 mL) with small amount of DMSO (10 mL) and added to the above-mentioned solution at −40° C. The reaction is stirred for additional 30 minutes before adding Et3N (11.7 g, 0.116 mol). The mixture is allowed to warm to room temperature and quenched with H2O (1 L). The organic layer is separated and washed with citric acid (10%, 500 mL), saturated NaHCO3 (500 mL) and brine (500 mL). It is dried with Na2SO4 to give 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-oxo-propyl)-amide; 1H NMR (DMSO-d6) δ 2.75 (dt, 2H, J1=1.2 Hz, J2=6.0 Hz), 3.61 (q, 2H, J=5.2 Hz), 7.06-7.17 (m, 2H), 7.45 (dd, 1H, J1=4.8 Hz, J2=8.8 Hz), 8.11 (t, 1H, J=5.6 Hz), 9.74 (t, 1H, 1.2 Hz), 12.10 (s, 1H); m/z [M++1] 361.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1>[CH:20]([O:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18])([CH3:22])[CH3:21]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 50.4 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 4.0 g (32.6 millimoles) of isopropyl chloroformate and 100 ml of absolute toluene are refluxed for 16 hours. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized twice from dimethylformamide/water. 4.3 g (50% of theory) of 4,5-dihydro-6-(p-isopropoxycarbonylaminophenyl)-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 236°-237° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2>ClCCl.C(OCC)C>[Cl:4][C:8]1[C:7]([OH:6])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: Oc1ccc2cnccc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Oc1ccc2cnccc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
0.61 mL (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6.9 mmol) of compound 7 in 30 mL of dichloromethane. Three drops diethyl ether were added and the reaction was stirred at room temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to give 1.1 g (89%) of compound 8 as a green-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]([CH3:15])[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:7]=1
Reactant: CN(Cc1nccs1)c1nc(Cl)nc(NN)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-6-hydrazino-N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (assumed dihydrochloride) (0.9034 g, 2.509 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (1.299 g, 3.01 mmol) were dissolved in DMF (13 mL). NMM (1.655 mL, 15.05 mmol) was added, followed by HOAt (0.4095 g, 3.01 mmol) and EDC (0.577 g, 3.01 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red sticky material. LCMS: (M+H)+=570.2.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].S([O:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])(C)(=O)=O.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CS(C)=O.[OH-].[Na+]>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OC[C@H](O)CO
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [CH2-]C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OC[C@H](O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of sodium hydroxide (39 g) in 200 ml water added to a rapidly stirred solution of (2R)-3-mesyloxy-1,2-propanediol acetonide (172.1 g) and 4-benzyloxyphenol (200 g) in 1.5 L dimethylsulfoxide, and the reaction was heated on a steam bath for 3 hours. The cooled solution was diluted with 1 L 1N sodium hydroxide solution and the resulting solids were washed with dilute sodium hydroxide solution with water. The air-dried solids were taken up in benzene (2 L) and the solution was dried over sodium sulfate, decolorized with charcoal and evaporated in vacuo. The product was dissolved in hot methanol (~1.5 L), cooled to ~40° and filtered free from some non-polar impurity. A small portion of the methanol solution was diluted with water to give (2S)-3-(4-benzyloxyphenoxy)-1,2-propanediol acetonide. Crystallization from hexane furnished the pure specimen, mp 69.5°-71°; [α]D25, +6.26° (c, 1.0, methanol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:36])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][N:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)[CH2:27][CH2:28]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:36])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCN2CCN(c3cc(C)ccn3)CC2)O4)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccnc(N2CCN(CCC3Cn4c(-c5ccc(O)cc5)c(C)c5cccc(c54)O3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
1.9 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[2-(4-(4-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrrolo[1,2,3-de]-1,4-benzoxazine (Preparation see Example 1) were dissolved in 5 ml of anhydrous dichloromethane under a nitrogen atmosphere. The solution was cooled to 0° to 5° C. and 1.5 g of boron tribromide were then added all at once. The reaction mixture was subsequently stirred for 3 hours at room temperature. The reaction mixture was then again cooled to 0° to 5° C. and 10 ml of methanol were added, and the reaction mixture was again stirred for half an hour at room temperature and then evaporated. The residue was dissolved in 20 ml of aqueous ammonia solution (pH=8/9) and the solution was extracted with dichloromethane. The extracts were dried, filtered and concentrated. The crude title compound remaining as a residue was purified by column chromatography using toluene/ethanol 95:5 and crystallized from isopropanol. 1.5 g of 2,3-dihydro-5-(4-hydroxyphenyl)-6-methyl-2-[2-(4-(4-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrrolo[1,2,3-de]-1,4-benzoxazine were obtained as a white powder having a melting point of 213° to 214° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:26])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([Cl:26])=[O:8])([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
A mixture of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (5 g) and thionyl chloride (50 ml) was heated on a steam bath for 5 hours. After evaporation in vacuo to dryness, the compound was obtained as a crude product, which was used in the next step without further purification.
Reaction SMILES: C([Al]CC(C)C)C(C)C.[CH3:10][CH:11]([CH2:16][C:17](OC)=O)[C:12](OC)=O.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]>ClCCl.O>[CH3:12][C:11]1[CH:16]=[CH:17][N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:10]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)CC(C)C(=O)OC
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccn(-c2ccccc2O)c1
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Diisobutylaluminum (100 mL of 1.0 M, 100 mmol) was added dropwise to a solution of dimethyl 2-methylbutanedioate (7.6 g, 48 mmol) in dichloromethane (15 mL) at −78° C., and the solution was stirred for 1 h. A suspension of 2-aminophenol HCl salt (6.6 g, 45 mmol) in water (110 mL) was added initially dropwise with vigorous stirring, then in small portions. About midway through the addition, the cooling bath was removed to help facilitate stirring. The mixture was stirred vigourously at room temperature overnight, then filtered over celite and the filter cake was washed several times with dichloromethane. The filtrate was separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, concentrated and purified by column chromatography (0-40% EtOAc/hexane) to give 2-(3-methylpyrrol-1-yl)phenol (3.7 g, 48%) as a yellow oil. ESI-MS m/z calc. 173.2, found 174.3 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: CC[C:3]1(C2C=CC=CC=2)[C:9](=O)[NH:8][CH2:7][NH:6][C:4]1=O.[N+:17]([O-])([OH:19])=[O:18].[OH-:21].[Na+]>S(=O)(=O)(O)O>[N+:17]([C:9]1[CH:3]=[CH:4][NH:6][C:7](=[O:21])[N:8]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCC1(c2ccccc2)C(=O)NCNC1=O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1nc([N+](=O)[O-])cc[nH]1
Temperature: 0 °C

Procedure:
Primidone, 1.60 g, was dissolved with stirring in 8 ml concentrated sulfuric acid and cooled in ice. A cold solution of 485 μl concentrated nitric acid in 2 ml concentrated sulfuric acid was added over a period of 10 minutes. After 2 hours at 0° C. the reaction mixture was poured into ice water neutralized with cold sodium hydroxide. The precipitate was collected, washed with water and dried in vacuo affording 1.79 g white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:18])[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:9][C:10]=3[CH:11]=2)[CH2:30][CH2:29]1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: OC1CCNCC1
Reactant: ClCCCCCCBr
Product: O=c1cc(-c2ccccc2)oc2cc(OCCCCCCN3CCC(O)CC3)ccc12

Procedure:
The compound was prepared by a method similar to Example 3 from 7-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 130°-131° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]([Cl:21])[C:12]2[N:13]([C:15]([C:18](Cl)=[O:19])=[CH:16][N:17]=2)[N:14]=1.[Br:22][C:23]1[C:24]2[N:25]([C:30]([C:33](Cl)=[O:34])=[CH:31][N:32]=2)[N:26]=[C:27]([Cl:29])[CH:28]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([Cl:21])[C:12]2[N:13]([C:15]([C:18]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1.[Br:22][C:23]1[C:24]2[N:25]([C:30]([C:33]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)=[O:34])=[CH:31][N:32]=2)[N:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: O=C(Cl)c1cnc2c(Cl)cc(Cl)nn12
Reactant: Nc1ccncn1
Reactant: O=C(Cl)c1cnc2c(Br)cc(Cl)nn12
Solvent: ClCCl
Product: O=C(Nc1ccncn1)c1cnc2c(Br)cc(Cl)nn12
Product: O=C(Nc1ccncn1)c1cnc2c(Cl)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
Pyrimidin-4-amine (251 mg, 2.64 mmol) was added to a ˜1:1 mixture of 6,8-dichloroimidazo[1,2-b]pyridazine-3-carbonyl chloride and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carbonyl chloride 14A (600 mg, 2.396 mmol) and TEA (0.334 mL, 2.396 mmol) in DCM (6 mL), and the reaction mixture was stirred at room temperature for 14 hrs. The reaction mixture was filtered via Buchner funnel The solid was washed with water, and dried under high vacuum to isolate 6,8-dichloro-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a brown yellow solid (726 mg, 98%), which was taken to next step without further purification. N-(4-methoxybenzyl)cyclopropanamine (381 mg, 2.148 mmol) was added to ˜1:1 mixture of 6,8-dichloro-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (467 mg, 1.432 mmol) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL). The reaction mixture was heated at 80° C. for 1.5 hrs. Water (20 mL) was added to the reaction mixture, and the solid was collected via Buchner filtration (with methanol wash) to isolate the title compound 6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 14A (519 mg, 78%) as a light yellow powder. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=2.107 (M+H=450.22).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([NH:9][C:10]2[N:11](C)[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=CC=3)=[CH:3]1.Cl[CH2:23]Cl.C([O:28][CH2:29][CH3:30])(=O)C>>[NH2:20][C:19]1[C:18]2[C:10]([NH:11][C:12]3[C:30]=2[C:29](=[O:28])[CH:15]=[CH:16][CH:17]=3)=[N:9][C:4]2=[C:5]([CH3:23])[CH:6]=[CH:7][CH:8]=[CH:2][C:3]=12
Reactant: ClCCl
Reactant: Cn1c(NC2=CC(=O)CCCC2)c(C#N)c2ccccc21
Reactant: CCOC(C)=O
Product: Cc1ccccc2c(N)c3c(nc12)[nH]c1cccc(=O)c13

Procedure:
Also isolated by chromatography was [(3-oxo-1-cyclohepten-1-yl)amino]-1-methyl-1H-indole -3-carbonitrile (D17) (1.30 g, 20%) Rf 0.19 (SiO2, 2:1 dichloromethane:ethyl acetate). This intermediate could be converted to the title compound (E16) using a procedure similar to that described in Description 6.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[ClH:17].[N:18]1(C(=N)N)[CH:22]=[N:21]C=N1.CCOCC>CN(C)C=O>[ClH:17].[N:1]1([C:22](=[NH:18])[NH2:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCCCCC1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of hexahydro-1H-azepine (5.63 ml, 50.0 mmol), diisopropylethylamine (8.73 ml, 50.0 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (6.11 g, 55 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature over the weekend. Ether (100 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The ether was decanted from the solid residue. The residue was stirred with ether (50 ml) at 5° C. (ice water bath) for 10 minutes and the ether layer was separated from the residue. Ether (50 ml) was added to the residue and the mixture was stirred at 5° C. The resulting solid was collected, washed with ether and dried to give the title compound as a colourless solid (6.8 g, 77%). LC/MS [M+H]+=142.