Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C1C=CC(C2C=CC(C(=C3CC(C)(C)CC(C)(C)C3)C3C=CC(O)=CC=3)=CC=2)=CC=1)(=O)=O.Br[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[C:50]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.[C:58]([C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1)#[N:59].C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[C:50]1(=[C:42]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[C:39]2[CH:38]=[CH:37][C:36]([C:63]3[CH:64]=[CH:65][C:60]([C:58]#[N:59])=[CH:61][CH:62]=3)=[CH:41][CH:40]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(C(=C3CCCCCCC3)c3ccc(O)cc3)cc2)cc1
Yield: 75.5 %

Procedure:
The Suzuki protocol described for (163) was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49) (0.140 g, 0.37 mmol), PdCl2(PPh3)2 (0.027 g, 0.05 mmol), (4-cyanophenyl)boronic acid (0.109 g, 1.0 mmol), aqueous 2 M Na2CO3 (0.7 mL, 0.74 mL, 0.079 g, 1.0 mmol) solution, and 4:1 THF:H2O mixture (5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 6 h. Upon regular work-up and purification gave 0.110 g (76%) of the title compound (239) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 7.86 (d, J=4.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.00 Hz, 2H), 7.24 (d, J=8.00 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.00 Hz, 2H), 2.21 (br s, 4H), 1.61 (br s, 2H), 1.49 (br m, 8H). LCMS (ESI): m/z 392.21 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (600 mg, 2.0 mmol) was reacted with tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (340 mg, 39%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 58 mg (56%) of the title compound as an off white solid.
Reaction SMILES: Br[C:2]1([F:19])[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:18][CH2:17][CH2:16][O:15]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[F:19][CH:2]1[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:15][CH2:16][CH2:17][O:18]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NOC1CC1(F)Br)C1(C)OCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC1CC1F)C1(C)OCCO1
Yield: 44.3 %

Procedure:
A solution of ethyl 2-(2-bromo-2-fluorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(4 g) and tri-n-butyltinhydride (2.28 ml) in benzene (30 ml) was refluxed under nitrogen atmosphere in the presence of 2,2'-azobisisobutyronitrile (250 mg) for 2 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with benzene. The fractions containing the compound, which had higher Rf-value on TLC [development solvent system: benzene], were collected and concentrated in vacuo to give ethyl 2-(2-fluorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(1.36 g).
Reaction SMILES: OC1N=C2C(C=CC(C34C=CC(Cl)=CC3C(NC4=O)=O)=N2)=CC=1.NC1C=CC2C(=NC(O)=CC=2)N=1.ClC1C=C2C(=O)OC(=O)C2=CC=1.ClC1N=C2C(C=CC(C34C=CC(Cl)=CC3C(NC4=O)=O)=N2)=CC=1.P(Cl)(Cl)(Cl)=O.[BH4-].[K+].[Cl:78][C:79]1[N:88]=[C:87]2[C:82]([CH:83]=[CH:84][C:85]([N:89]3[CH:97]([OH:98])[C:96]4[C:91](=[CH:92][C:93]([Cl:99])=[CH:94][CH:95]=4)[C:90]3=[O:100])=[N:86]2)=[CH:81][CH:80]=1>C(O)(=O)C.CO.O1CCOCC1.CN(C)C=O>[Cl:78][C:79]1[N:88]=[C:87]2[C:82]([CH:83]=[CH:84][C:85]([N:89]3[CH:90]([OH:100])[C:91]4[C:96](=[CH:95][CH:94]=[C:93]([Cl:99])[CH:92]=4)[C:97]3=[O:98])=[N:86]2)=[CH:81][CH:80]=1
Reactant: O=C1c2cc(Cl)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: Nc1ccc2ccc(O)nc2n1
Agent: O=C1NC(=O)C2(c3ccc4ccc(Cl)nc4n3)C=CC(Cl)=CC12
Agent: O=C1NC(=O)C2(c3ccc4ccc(O)nc4n3)C=CC(Cl)=CC12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1c2ccc(Cl)cc2C(O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Preparation of 2-(7-hydroxy-1,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g.), m.p. 320° C., by reacting 2-amino-7-hydroxy-1,8-naphthyridine (9.5 g.) with 4-chlorophthalic anhydride (21.5 g.) in acetic acid (450 cc.) for 1 hour at 116° C. Preparation of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide (6.4 g.), m.p. 280° C., by reacting phosphorus oxychloride (70 cc.) with 2-(7-hydroxy-1,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g.) in the presence of dimethylformamide (0.7 cc.). By reacting potassium borohydride (0.75 g.) with 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide (6.4 g.) in a mixture (300 cc.) of dioxan and methanol(50-50 by volume), a mixture (5.2 g.) of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one and 2-(7-chloro-1,8-naphthyridin-2-yl)-6-chloro-3-hydroxy-isoindolin-1-one is obtained. This mixture is recrystallised firstly from dichloroethane (700 cc.) and then a second time from the same solvent (315 cc.). A product (1.51 g.) is thus obtained and is recrystallised successively from bromoform (38 cc.) and then from a mixture (104.5 cc.) of dichloroethane and ethanol (91-9 by volume). 2-(7-Chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one (0.65 g.) is thus obtained. Preparation of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxycarbonyloxy-isoindolin-1-one (1.6 g.), m.p. 220°-230° C., from 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one (1 g.) and phenyl chloroformate (1.36 g.) in anhydrous pyridine (15 cc.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].O.[OH-].[Li+].CO.O>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(C#N)cc2F)c(F)c(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
In a 50-mL round bottom flask, equipped with a stir bar, methyl 4-amino-3-chloro-6-(4-cyano-2-fluorophenyl)-5-fluoropicolinate (351 mg, 1.084 mmol) and lithium hydroxide hydrate (100 mg, 2.383 mmol) were dissolved in tetrahydrofuran (2.0 mL), methanol (2.0 mL) and H2O (1.0 mL). The reaction was stirred at room temperature for 2 hours. The solvent was then removed by rotary evaporator. The resulting solid was treated with H2O, which was then adjusted to pH-3.0 with 1 N HCl, and extracted with ethyl acetate (3× 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (150 g C18, 0-100% acetonitrile in H2O), as needed, to afford the title compound as a white solid (0.058 g, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:28][CH:27]=1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:28][CH:27]=1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1oc2cc(O)c(Br)cc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Yield: 25.5 %

Procedure:
A solution of 6-bromo-7-methoxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-one (0.20 g, 0.3 mmol) and hydrogen bromide in acetic acid (10 mL) was heated to reflux overnight. After cooling, excess acetic acid was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in succession; dried over magnesium sulfate; filtered; and concnetrated under reduced pressure to afford crude product. Purification using reverse-phase preparatory HPLC (20–80% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) provided fractions that were subsequently neutralized with sodium bicarbonate and extracted using ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (>98% pure, 45.0 mg, 23%). 1H NMR (300 MHz, d6-DMSO) δ 7.78 (m, 2H), 7.69 (s, 1H), 7.55 (m, 2H), 7.08 (m, 2H), 6.88 (s, 1H), 6.83 (m, 2H), 4.04 (t, 2H), 3.94 (s, 2H), 2.92 (t, 2H), 2.67 (bm, 4H), 1.72 (bm, 4H). MS (ESI) m/z 588.3 (M+1)+, 590.3 (M+1+2)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][S:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCSCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 6 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and thiomorpholine as starting materials, 19 mg (6%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (d, 2 H), 2.6 (t, 8 H); ES-MS m/z 532.07 [M+H]+, HPLC RT (min) 2.34.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:18][C:19](=[O:29])[CH2:20][NH:21]C(=O)OC(C)(C)C)[B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:16])[CH3:15].Cl>C(Cl)Cl.O1CCOCC1>[NH2:21][CH2:20][C:19]([NH:18][C@H:4]([B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:15])[CH3:16])[CH2:3][CH:2]([CH3:30])[CH3:1])=[O:29]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]carbamate (2.5 g, 5.9 mmol) in DCM (15 mL) was added 4M HCl in dioxane (5.9 mL). The reaction mixture was allowed to stir for 2 h and concentrated to give 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CNCCN1CCOCC1
Agent: N
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: CN(CCN1CCOCC1)c1nnc2ccc(F)cn12
Temperature: 170 °C
Yield: 72 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and Intermediate 45b (1.26 g, 8.77 mmol) in NMP (2 mL) was heated in the microwave at 170° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as an orange oil (350 mg, 71%). 1H NMR (400 MHz, CDCl3): 2.41-2.52 (4H, m), 2.58 (2H, t, J 5.6), 3.03 (3H, s), 3.27 (2H, t, J 6.0), 3.62 (4H, t, J 5.2), 7.04-7.08 (1H, m), 7.58-7.65 (1H, m), 8.39 (1H, t, J 2.4).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8](O)=O)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[N:19]1[O:20][N:21]=[C:22]2[CH:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[CH:24][C:23]=12.S(=O)(=O)(O)O>ClCCl.O.CCCCCC.C1COCC1>[CH:2]12[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3]1)[CH2:8][N:1]2[C:28]([C:26]1[CH:25]=[CH:24][C:23]2=[N:19][O:20][N:21]=[C:22]2[CH:27]=1)=[O:29]
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=C(c1ccc2nonc2c1)N1CC2CCC1CC2
Temperature: 25 °C
Yield: 76 %

Procedure:
Cis-4-Aminocyclohexanecarboxylic acid (2.0 g 13.96 mmol) was heated in a flask with a heat gun for 15 minutes. After cooling to room temperature, THF (70 ml) was added followed by lithium aluminum hydride (4 g), slowly and portion wise, and the mixture heated at 65° C. for 1 h. The mixture was cooled, and hexane (70 ml) and sodium hydroxide solution (5 ml) were added whilst rapidly stirring. Celite (5 g) was added and the mixture stirred overnight. The solids were removed by filtration and washed with THF (10 ml). Triethylamine (4 ml) was added followed by a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (2.0 g, 10.95 mmol) in dichloromethane (15 ml) and the mixture was stirred at room temperature for 0.3 h. Water (100 ml) was added, acidified to pH 2 with sulfuric acid and extracted with ethyl acetate (2×100 ml). The combined organics were washed with saturated sodium bicarbonate solution (100 ml), dried (NaSO4) and evaporated under vacuum. The residue was chromatographed on silica gel eluting with ethyl acetate/dichloromethane/hexane (40:10:50) to give the desired product as a white solid (2.14 g): mp=138-139° C., LC-MS, MH+=258; 1H NMR (300 MHz, CDCl3, rotamers) δ 7.91 (dd, J=1.2 and 9.3 Hz, 1H), 7.90 and 7.83 (dd, J=1.2 and 1.2 Hz, total 1H), 7.51 and 7.46 (dd, J=1.2 and 9.3 Hz, total 1H), 4.58 and 3.42 (br s, total 1H), 3.68-2.64 (m, 2H), 2.12-1.61 ppm (m, 9H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.Cl>CS(C)=O.CS(C)=O.CCOCC.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Br)cc2)CCCC1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (2.55 g, 63.75 mmol, 60%) in dimethyl sulfoxide (50 mL) were added dropwise a mixture of 4-bromophenyl-acetonitrile (223) (5 g, 25.51 mmol) and 1,4-dibromobutane (3.04 mL, 25.51 mmol) dissolved in dimethyl sulfoxide:ether (1:1) (50 mL) at 0° C. and the reaction mixture was stirred at this temperature for 2 h. After completion of the reaction, water (20 mL) and 10% HCl solution (50 mL) were added to the mixture and the mixture was extracted with ethyl acetate (2×200 ml). The organic layer was dried over Na2SO4, concentrated and purified by 100-200 silica column chromatography using hexane as the eluent to give 1-(4-bromophenyl)-cyclopentanecarbonitrile (224) (5.7 g, 89%) as a white crystalline solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[CH3:19][C:20]([CH3:58])([CH3:57])[CH2:21][N:22]1[CH2:35][C:27]2[C:28]3[CH:29]=[N:30][NH:31][C:32]=3[CH:33]=[CH:34][C:26]=2[CH2:25][C@H:24]([CH2:36][C:37](=[O:55])N2CCC(N3CC4C(=CC=CC=4)NC3=O)CC2)[C:23]1=[O:56]>>[CH2:21]([N:22]1[C:23](=[O:56])[C@H:24]([CH2:36][C:37](=[O:55])[N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[C:9](=[O:18])[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:6][CH2:7]2)[CH2:25][C:26]2[CH:34]=[CH:33][C:32]3[NH:31][N:30]=[CH:29][C:28]=3[C:27]=2[CH2:35]1)[C:20]([CH3:58])([CH3:57])[CH3:19]
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 31 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 31% yield. MS m/e (M+H)+=540.2. 1H NMR (500 MHz, DMSO-D6): δ=11.76 (s, 1H), 8.22 (s, 1H), 7.70 (d, J=8.85, 1H), 7.62 (s, 1H), 7.43 (t, J=7.48, 1H), 7.37 (d, J=8.55, 1H), 7.28 (d, J=8.24, 1H), 7.15 (t, J=7.32, 1H) 7.11 (d, J=8.55, 1H), 5.38 (d, J=17.09, 1H), 4.62 (d, J=16.79, 1H), 4.55 (d, J=11.29, 1H), 4.13 (s, 1H), 3.88 (s, 1H), 3.58 (s, 2H), 3.16 (m, 2H), 3.07 (m, 3H), 2.88 (t, J=14.34, 1H), 2.64 (m, 1H), 2.36 (m, 1H), 1.92 (d, J=10.38, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.73 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C=O)C.CCOCC>[CH2:13]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])[CH:12]=[CH2:11]
Reactant: C#CC(O)CC(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(CC(C)C)OCC=C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
A solution of 5-methylhex-1-yn-3-ol (2.11 g, 18.81 mmol) in DMF (30 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.903 g, 22.57 mmol). The reaction was stirred for 20 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (4.9 ml, 56.6 mmol) over 5 min. The reaction was stirred overnight. The reaction was diluted with Et2O (100 mL), washed with water (4×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give the product, 3-(allyloxy)-5-methylhex-1-yne (2.83 g, 13.94 mmol, 74.1% yield) as a yellow mobile oil. 1H NMR consistent with expected product, contains ca. 4:1 product/SM. Used as-is without further purification. 1H NMR (CDCl3) δ: 5.89-6.00 (m, 1H), 5.34 (dq, J=17.2, 1.6 Hz, 1H), 5.22 (dq, J=10.3, 1.4 Hz, 1H), 4.29 (ddt, J=12.6, 5.1, 1.5 Hz, 1H), 4.14 (ddd, J=7.6, 6.7, 2.0 Hz, 1H), 3.99 (ddt, J=12.6, 6.3, 1.3 Hz, 1H), 2.44 (d, J=2.0 Hz, 1H), 1.90 (dsxt, J=13.5, 6.8 Hz, 1H), 1.64-1.80 (m, 2H), 1.56-1.64 (m, 2H), 0.95 (d, J=4.6 Hz, 3H), 0.94 (d, J=4.6 Hz, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:14]=[N:13][C:12]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]=2[CH:10]=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:23]1(/[CH:29]=[CH:30]/[C:9]2[N:14]=[N:13][C:12]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C:11]=3[CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Reactant: OB(O)/C=C/c1ccccc1
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: Cc1ccccc1
Solvent: O
Product: C(=C/c1cc2c(nn1)Oc1ccccc1O2)\c1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 49.2 %

Procedure:
Toluene (10 ml) was added to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (600 mg), and (E)-2-phenylvinylboronic acid (480 mg), tetrakis(triphenylphosphine)palladium (315 mg) and 2M aqueous sodium carbonate solution (1.6 mL) were added at room temperature. The reaction mixture was stirred at 120° C. for 14 hr. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and ethyl acetate and filtered. The obtained solid was dried under reduced pressure to give 3-[(E)-2-phenylvinyl][1,4]benzodioxino[2,3-c]pyridazine (386 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:30][S:31]C.[Na]>C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:23]([CH3:29])=[N:24][C:25]([S:31][CH3:30])=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSC
Reactant: Cc1nc(Cl)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Agent: [Na]
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[5-(6-chloro-2-methyl-pyridin-3-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (160 mg) and sodium methyl sulfide (84 mg) in N,N-dimtehylformamide (1.6 mL) is stirred for 4 h at 80° C. Three more portions of sodium methyl sulfide (28 mg each) are added over the course of two days while stirring the reaction mixture at 80° C. until completion of the reaction. The reaction mixture is diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The crude product is used without further purification for the next reaction step. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=427 [M+H]+.