Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][OH:11].CC1CCCO1.[Cl:19][C:20]1[S:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=1>O.C1(C)C=CC=CC=1>[OH:12][C@H:9]([CH2:10][OH:11])[CH2:8][NH:7][C:25]([C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:26]
Reactant: NC[C@H](O)CO
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC1CCCO1
Solvent: O
Product: O=C(NC[C@H](O)CO)c1ccc(Cl)s1
Temperature: 16.5 °C

Procedure:
461 g of sodium hydrogencarbonate and 350 g of (2S)-3-aminopropane-1,2-diol hydrochloride (VII) (commercially available) are initially charged at from 13 to 15° C. in 2.1 l of water and admixed with 950 ml of 2-methyltetrahydrofuran. 535.3 g of 5-chlorothiophene-2-carbonyl chloride (approx. 93%) in 180 ml of toluene are added dropwise to this mixture with cooling at from 15 to 18° C. over a period of two hours. For workup, the phases are separated and the organic phase is admixed in several steps with a total of 1.5 l of toluene. The precipitated product is filtered off with suction, washed with ethyl acetate and dried.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]([OH:36])([CH3:34])[CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(C)(C)O)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To the solution of 8-5 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-6 (37 mg, yield 92.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1.COC(OC)OC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:35]3[CH2:36][O:33][CH2:34]3)[CH2:11][CH2:10]2)[C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:26][CH2:27]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1NC1CCNCC1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CO
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1NC1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
A suspension of 2-((2-chloro-5-cyano-4-(piperidin-4-ylamino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 410) (36 mg, 0.080 mmol), oxetan-3-one (116 mg, 1.604 mmol), trimethylorthoformate (0.443 mL, 4.01 mmol), and acetic acid (0.046 mL, 0.802 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 15 min. Sodium cyanoborohydride (1M in THF, 0.802 mL, 0.802 mmol) was added and the reaction was left stirring for 9 hrs. It was partitioned between EtOAc and sat. aq. NaHCO3 solution. After stirring for 15 min, the aqueous phase was separated and washed with EtOAc (3×) and then a mixture of 10% MeOH in DCM (4×). The combined organic phases were dried with sodium sulfate and the solvent removed. Preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 10-100% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) afforded the title compound (13 mg).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7](=[O:24])[O:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([CH3:22])=[C:11]([Cl:23])[CH:10]=2)C.[Br:26]N1C(=O)CCC1=O.Cl>C(OCC)(=O)C.C(O)(=O)C>[Br:26][CH2:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:23])[O:8][C:7](=[O:24])[C:6]([CH2:5][C:4]([OH:3])=[O:25])=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(C)c(Cl)cc2oc1=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc(CBr)c(Cl)cc2oc1=O

Procedure:
A solution of ethyl(7-chloro-6-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate (3.5 g) in ethyl acetate (50 ml) was combined with N-bromosuccinimide (2.1 g) and 2,2′-azoisobutyronitrile (48.3 mg), and heated under reflux for 1 hour. After cooling, the reaction solution was washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate-hexane=1:4) to obtain the crude crystal (approximately 2.6 g) of ethyl 2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetate. The crude crystal was dissolved in acetic acid (50 ml) and concentrated hydrochloric acid (25 ml), and heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain a crude crystal (1.78 g, yield: 44%) of the title compound. The compound was used in the next reaction without further purification. NMR (CDCl3) δ: 3.43 (2H, s), 4.58 (2H, s), 7.11 (1H, s), 7.20-7.30 (2H, m), 7.48 (1H, s), 7.50-7.65 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nccnc1N
Solvent: CC#N
Product: COC(=O)c1nc(Br)cnc1N
Yield: 92.3 %

Procedure:
A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N-bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at room temp overnight. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (11.68 g, 92% Yield); 1H NMR (400.0 MHz, DMSO) 3.85 (s, 3H), 7.55 (br s, 2H) and 8.42 (s, 1H) ppm; MS (ES+) 233
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)(=[O:41])=[O:40])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)N1CCOCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}morpholine-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and morpholine-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: O.O.Cl[Sn]Cl.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1.Cl>CCO>[Cl:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cn1ccnc1Sc1ccc(N)cc1Cl
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a solution of SnCl2.2H2O in EtOH (10 ml) at 60° C. was added 426A (1.80 g, 6.67 mmol). Concentrated HCl (8 ml) was added and the mixture was heated at 60° C. for 15 min. Cooled to rt, the mixture was concentrated under reduced pressure. The residue was basified to pH>12 and extracted with EtOAc (4×50 ml). The combined organic layers were washed with 1N KOH (20 ml), H2O (20 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave 426B (1.31 g, 82%) as a white solid. The solid was used in next step without further purification. It has a retention time of 3.53 min (standard LC1 method, 8 min run). MS Found: (M+H)+=240.1
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:12])[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.[Cl:39][CH:40]([Cl:59])[C:41]([N:43]1[C@H:47]([CH2:48][F:49])[C@@H:46]([C:50]2[CH:55]=[CH:54][C:53](I)=[CH:52][CH:51]=2)[O:45][C:44]1([CH3:58])[CH3:57])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:59][CH:40]([Cl:39])[C:41]([N:43]1[C@H:47]([CH2:48][F:49])[C@@H:46]([C:50]2[CH:55]=[CH:54][C:53]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([F:12])[CH2:11][O:10][CH2:9]4)=[N:6][CH:7]=3)=[CH:52][CH:51]=2)[O:45][C:44]1([CH3:57])[CH3:58])=[O:42]
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: FC1(c2ccc(Br)cn2)COC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C4(F)COC4)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 85 °C
Yield: 81.1 %

Procedure:
To a degassed solution of the product of step 1, Example 17 (300.0 mg, 1.29 mmol), bis(pinacolato)diboron (354 mg, 1.39 mmol), and potassium acetate (342 mg, 3.48 mmol) in 1,4-dioxane (4.65 mL) is added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (81.2 mg, 0.099 mmol) and the reaction mixture is heated at 80-90° C. After 3 hours (4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-1,3-oxazolidine (see WO2013057619, 444 mg, 0.994 mmol) is added to the reaction mixture followed by a degassed solution of sodium carbonate (422 mg, 3.98 mmol) in water (2.5 mL). The reaction mixture is heated at 80-90° C. for 4 hours before being cooled to room temperature, diluted with ethyl acetate, and washed with water, then brine, dried, and concentrated. The residue is purified by chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexanes to afford the title compound (380 mg): MS (ESI+) m/z of 471.1/473.0 [M+H].
Reaction SMILES: [CH3:1][C:2]([NH:13]C(=O)OC(C)(C)C)([CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[ClH:21]>C(OCC)(=O)C>[ClH:21].[NH2:13][C:2]([CH3:3])([CH3:1])[CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(CC(=O)N1CCOCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(N)CC(=O)N1CCOCC1
Reaction time: 3 h

Procedure:
tert-Butyl 2-methyl-4-morpholino-4-oxobutan-2-ylcarbamate (0.5 g, 1.7 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (20 mL). The mixture was stirred for 3 h. The solvent was removed by reduced pressure to give crude product (0.55 g).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:22]OC1C=C2C(C(C(C)C(O)=O)=CN=C2N2CCOCC2)=CC=1>>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6][N:5]=1)([CH3:22])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C(C)C(=O)O)cnc(N3CCOCC3)c2c1
Reactant: COc1cc2c(CC(=O)O)cnc(C(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)O)cnc(C(C)(C)C)c2cc1OC

Procedure:
(1-Isopropyl-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid, characterised as the ethyl ester 1H NMR (400 MHz, CDCl3) δ 1.25 (t J 7 3H), 1.45 (d J 7 3H), 3.82 (heptet J 7 1H), 3.90 (s 2H), 3.08 (s 2H), 4.15 (q J 7 2H), 7.28 (s 1H), 7.48 (s 1H), 8.30 (s 1H). Intermediate 41: 2-(7Methoxy-1-morpholin-4-yl-isoquinolin4-yl)-propionic acid mp 225-227° C., is prepared according to the procedure for Intermediate 27.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:50]([N:52]([CH2:57][CH3:58])[CH2:53][CH2:54][CH2:55]O)[CH3:51].C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C>C1COCC1>[Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:55][CH2:54][CH2:53][N:52]([CH2:57][CH3:58])[CH2:50][CH3:51])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Reactant: CCN(CC)CCCO
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.2 %

Procedure:
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (180 mg, 0.41 mmol, 1 eq.), triphenylphosphine (430 mg, 1.64 mmol, 4 eq.) and 3-(diethylamino)propan-1-ol (264 mg, 2.05 mmol, Seq.) in THF (10 ml) was added diisopropyldiazodicarboxylate (DIAD, 332 mg, 1.64 mmol, 4 eq.). The resulting solution was stirred at room temperature under Ar for 20 h and concentrated under reduced pressure. The crude residue was chromatographed over silica gel column (eluted with mixtures of AcOEt and EP and then AcOEt and MeOH). The product was then dissolved in dichloromethane and precipitated with EP. The solid was then filtered and washed with EP to give 3-(4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenoxy)-N,N-diethylpropan-1-amine (113 mg, 0.21 mmol, 51% yield). 1H NMR (CDCl3 300 MHz) δ ppm 8.47 (dd, 2H, J=2.6 Hz, 8.3 Hz), 8.18 (d, 1H, J=2.3 Hz), 8.13 (d, 2H, J=7.4 Hz), 8.01 (d, 1H, J=1.5 Hz), 7.77 (dd, 1H, J=1.8 Hz, 8.7 Hz), 7.54 (dd, 3H, J=8.7 Hz, 9.0 Hz), 7.42 (dd, 2H, J=7.3 Hz, 7.9 Hz), 7.01 (d, 2H, J=8.6 Hz), 4.08 (t, 2H, J=6.1 Hz), 2.58-2.72 (m, 6H), 2.00 (dd, 2H, J=6.8 Hz, 7.5 Hz), 1.08 (t, 6H, J=7.2 Hz). NMR 13C 75 MHz CDCl3 δ ppm 162.5 (C), 158.9 (C), 149.3 (C), 145.6 (CH), 138.6 (C), 137.5 (C), 137.4 (C), 134.3 (CH), 129.1 (2×CH), 128.3 (2×CH), 128.3 (C), 128.1 (CH), 127.6 (2×CH), 122.4 (C), 120.1 (C), 118.8 (CH), 115.5 (CH), 115.1 (2×CH), 66.5 (CH2), 49.5 (CH2), 47.1 (2×CH2), 26.8 (CH2), 11.6 (2×CH3). MS [ESI] 548 [M+H 35Cl], 550 [M+H 37Cl].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29]>C(Cl)Cl.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([I:29])[C:7]([NH2:10])=[N:6][CH:5]=1
Reactant: [IH2+]
Reactant: COC(=O)c1ccc(N)nc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 5 g 6-Amino-nicotinic acid methyl ester and 16.2 g Bis(pyridine)iodonium(I) tetrafluoroborate in 250 mL DCM, 7.6 mL Trifluoromethanesulfonic acid were added dropwise at 0° C. The mixture was stirred for 24 h at RT. Then additional 3.2 g Bis(pyridine)iodoniun(I) tetrafluoroborate and 1.5 mL Trifluoromethanesulfonic acid were added. After stirring for 2 h at RT the reaction mixture was concentrated under reduced pressure and then taken-up with concentrated aqueous Na2SO3 solution and brought to pH 8 with concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with brine and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was codestilled with 100 mL toluene. Yield: 9.6 g.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17].C(OCC)C>ClCCl>[O:12]=[CH:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]
Reactant: CC(C)COC(=O)/C=C/CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)COC(=O)/C=C/C=O
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of pyridinium chlorochromate (100 g, 0.463 mol) in dichloromethane (350 ml), a solution of isobutyl (E)-4-hydroxycrotonate (50 g, 0.316 mol) in dichloromethane (150 ml) was added. The internal temperature gradually rose to 40° C. and stirring was continued for 2 hours without cooling. Diethyl ether (0.9 l) was added and the supernatant was decanted from the black gum. The insoluble residue was washed twice 300 ml portions of diethyl ether. The combined organic solutions were passed through a short pad of Florisil and the solvent was removed by distillation, to yield 45.3 g (91.6%) of the title compound, as a pale yellow oil, Rf=0.5 (silica gel plates, cyclohexane-ethyl acetate 6:4). NMR (CDCl3): deltaH =9.80 (ABX, 1H, CHO), 6.98 and 6.75 (ABX, JAB =15 Hz, 2H, CH=CH). MS (E.I., 70 eV, 1.5 mA) m/z=155 (M--H)+, 85 (M--C3H3O2)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.O=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17](OC)=[O:18])[CH2:11]1.O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:4]1[CH:3]=[CH:2][N:1]2[CH2:6][CH2:7][N:8]3[C:17](=[O:18])[CH2:16][CH:12]4[CH2:13][C:14]3([CH2:15][CH2:10][CH2:11]4)[C:5]=12
Reactant: COC(=O)CC1CCCC(=O)C1
Reactant: NCCn1cccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC2CCCC3(C2)c2cccn2CCN13

Procedure:
A solution of 1.3 g of 2-(1-pyrrolyl)-ethylamine, 2.0 g of methyl 3-oxocyclohexylacetate in 150 ml toluene is stirred and refluxed overnight using a Dean Stark water separator. The reaction is cooled and 7 ml glacial acetic acid is added. The solution is stirred and refluxed as before for 6 hours, cooled and the organic solvents are evaporated under reduced pressure. The residue is dissolved in ether and washed with ice cold 1N aqueous sodium hydroxide. The organic layer is separated, dried over magnesium sulfate, and filtered. The ether solution is evaporated under reduced pressure and the residue is crystallized from ether to give 5,6,10,11,12,13-hexahydro-10,13a-methano-13aH-pyrrolo[2',1':3,4]pyrazino[1,2-a]azocin-8(9H)-one, m.p. 130°-132°, the compound of formula II wherein R, R1R2 and R3 represent hydrogen.
Reaction SMILES: C[N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:26][CH2:25][O:24][C:22]([CH:3]1[CH:4]2[N:5]([C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=32)[CH2:19][CH2:20][NH:2]1)=[O:23]
Reactant: CN1CCN2c3ccccc3Oc3ccccc3C2C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCN2c3ccccc3Oc3ccccc3C12
Yield: 80 %

Procedure:
A solution of 2-methyl-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]oxazepine) (2.0 g, 7.5 mmol, prepared similarly as described in Neth. Appl. 6709520, Chem. Abs. 70, 115192 (1969)) in toluene (12 ml) was added drop wise to a stirred solution of ethyl chloroformate (1.26 g, 1.1 ml, 11.7 mmol) in toluene (8 ml) at 60° C. The mixture was heated at reflux temperature for 2 h. After cooling, the mixture was washed with a saturated solution of sodium bicarbonate (2×10 ml), water (10 ml), dried (MgSO4) and evaporated. The residue (2.5 g) was purified by column chromatography on silica gel (50 g) using benzene as eluent to give 1.95 g (80%) of 2-ethoxycarbonyl-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]oxazepine) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH2:7][CH2:2][CH2:3][CH3:4])[S:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)c2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCSc1nc2c(Br)cc(C)cc2s1
Yield: 66 %

Procedure:
To 10 ml of tetrahydrofuran solution containing 0.52 g of 4-bromo-2-mercapto-6-methylbenzothiazole was added 50 mg of sodium hydride at 0° C. After adding 0.28 g of n-bromobutane, the whole mixture was refluxed for 2 hours, distilled under reduced pressure to remove tetrahydrofuran and then extracted with ethyl acetate by adding water and ethyl acetate. The ethyl acetate layer was dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound in a yellow liquid state (Yield: 66%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17]>CN(C)C=O>[CH3:15][O:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: COCCl
Reactant: Oc1cccc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g 5,6,7,8-tetrahydro-naphthalen-1-ol was dissolved in 20 ml of N,N-dimethylform-amide. To this solution was added slowly 0.256 g of 95% NaH, followed by addition of 0.768 ml of chloromethoxymethane. The reaction was flushed with nitrogen and left stirring overnight at room temperature. The reaction mixture was then diluted with 50 ml of water and extracted with 50 ml of diethyl ether. The organic layer was washed with 50 ml of water, dried over magnesium sulphate and concentrated in vacuo to afford a crude oil. This was purified by flash chromatography (silica, heptanes/dichloro-methane) to afford 1.0 g of 5-methoxymethoxy-1,2,3,4-tetrahydro-naphthalene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:17]1[N:22]=[C:21]2[N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:34][CH2:33][CH2:32][C:31]=4[CH:35]=3)[N:24]=[N:25][C:20]2=[N:19][CH:18]=1.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:17]2[N:22]=[C:21]3[N:23]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:34][CH2:33][CH2:32][C:31]=5[CH:35]=4)[N:24]=[N:25][C:20]3=[N:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (37 mg, 0.165 mmoL) in anhydrous DMF (2 mL) was added NaH (60% in oil, 7 mg, 0.18 mmol). The solution was stirred at 23° C. for 15 minutes. 6-Bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (50 mg, 0.15 mmol) was added and the reaction solution was microwaved at 100° C. for 30 min. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined extracts were dried with Na2SO4, and concentrated to provide {(R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (67 mg, 99% yield).