Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([S:17]([N:20]2[CH:31]=[CH:30][C:29]3[C:21]2=[N:22][CH:23]=[C:24]2[C:28]=3[N:27]([CH:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)[N:26]=[N:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([S:17]([N:20]2[CH:31]=[CH:30][C:29]3[C:21]2=[N:22][CH:23]=[C:24]2[C:28]=3[N:27]([CH:32]3[CH2:33][CH2:34][C:35](=[O:38])[CH2:36][CH2:37]3)[N:26]=[N:25]2)(=[O:18])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn(C3CCC(O)CC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of oxalyl chloride (665.5 mg, 5.24 mmol) in anhydrous dichloromethane (40 mL) was added anhydrous dimethylsulfoxide (0.44 mL, 9.12 mmol) at −78° C. under nitrogen, followed by stirring for 15 minutes. Then the reaction temperature was warmed to −20° C. and a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol (750 mg, 1.94 mmol) in anhydrous dichloromethane (10 mL)was added dropwise. The mixture was stirred at −20° C. for 15 minutes and warmed to room temperature. Triethylamine (2.15 g, 19.4 mmol) was added and the mixture was stirred for 90 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was crystallized form ethanol to give 600 mg (78%) of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanone as a solid. 1H NMR (400 MHz, CDCl3) δ: 9.29 (s, 1H), 8.24-8.22 (m, 3H), 7.81-7.64 (m, 4H), 5.67-5.65 (m, 1H), 2.91-2.83 (m, 2H), 2.52-2.49 (m, 6H),
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[C:14]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])=O>[OH-].[Na+].[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[CH2:14][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccccc1C(=O)c1cccc(-c2ccc3ccccc3c2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccccc1Cc1cccc(-c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 50 h
Yield: 94.7 %

Procedure:
First, 121 g of 2-[3-(2-naphthyl)benzoyl]benzoic acid were dissolved in 10 L of a 1N sodium hydroxide solution, and then a zinc powder activated with an aqueous solution of copper sulfate was added to the solution. The reaction solution was stirred for 50 hours under ref lux. After having been cooled to room temperature, the reaction solution was filtrated. The filtrate was acidified, and then the resultant solid was washed with boiling water. Thus, 110 g of 2-[3-(2-naphthyl)benzyl]benzoic acid were obtained (in 90% yield)
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]1([S:7]([CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CS(=O)c1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
To a stirred solution of 1.0 g (2.19 mmole) of the title product of Example 2 in 30 ml of cold (ca. 0°) dichloromethane was added 0.463 g (2.19 mmole) of 81% m-chloroperoxybenzoic acid. After about ninety minutes, 5 ml of saturated aqueous sodium thiosulfate was added. The mixture was washed sequentially with three portions of saturated aqueous sodium bicarbonate and three portions of water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tht title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CNC1CCCCC1NC>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([N:26]2[CH:27]=[CH:28][C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:25]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-n2ccc(-c3ccccc3)n2)cc(OCc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
3-(Benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (50 mg, 0.170 mmol), 3-phenyl-1H-pyrazole (29 mg, 0.201 mmol), K2CO3 (47.0 mg, 0.340 mmol), CuI (2 mg, 10.50 μmol), and N,N′-dimethyl-1,2-cyclohexanediamine (6 μl 0.038 mmol) were combined in 1,4-dioxane (0.5 mL) in a screw cap vial. The vial was sealed then heated to 110° C. After stirring overnight the mixture was cooled to RT. CuI (2 mg) and N,N′-dimethyl-1,2-cyclohexanediamine (6 uL) were added and heating continued at 110° C. After stirring overnight the mixture was cooled to RT and diluted with EtOAc. The resulting mixture was filtered and concentrated. The crude material was purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-70% CH3CN/water over 20 min at 20 mL/min) to give the title compound (33 mg, 54%) as an amber film. 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J=7.7 Hz, 2 H); 7.61 (d, J=2.5 Hz, 1 H); 7.50-7.32 (m, 9 H); 7.12 (d, J=2.6 Hz, 1 H); 6.73 (d, J=2.5 Hz, 1 H); 5.21 (s, 2 H); 3.68 (s, 3 H). LC/MS (M+H)+ 358.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9][CH:8]=1.[Br:16][C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23](I)=[CH:24][CH:25]=3)[C:20]3([CH2:35][S:34][C:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32]3)[C:19]=2[CH:18]=1.COCCOC>CCOC(C)=O.O>[Br:16][C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23]([C:11]4[CH:12]=[N:7][CH:8]=[N:9][CH:10]=4)=[CH:24][CH:25]=3)[C:20]3([CH2:35][S:34][C:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32]3)[C:19]=2[CH:18]=1
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a mixture of sodium carbonate (1.562 g, 14.74 mmol), palladium tetrakistriphenylphosphine (0.454 g, 0.393 mmol), pyrimidin-5-ylboronic acid (0.791 g, 6.39 mmol) and 2′-bromo-N-tert-butyl-7′-iodo-5H-spiro[thiazole-4,9′-xanthen]-2-amine (2.600 g, 4.91 mmol) in a resealable pressure tube, was added DME (15 mL) and water (5 mL) at RT. The tube was sealed and heated to 80° C. After 24 hrs, the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. The organic fraction was adsorbed onto silica gel and purified by silica gel chromatography using 40% hexanes:EtOAc to afford 2′-bromo-N-tert-butyl-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine. MS: MH+=481.0/483.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C>ClCCl.CN(C=O)C.ClCCCl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[N:28]([O:29][CH3:30])[CH3:27])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N(C)OC)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
A solution of pyridine-2,5-dicarboxylic acid-5-methyl ester (1.0 g, 5.52 mmol), 1,1′-carbonyldiimidazole (0.984 g, 6.07 mmol), 1,2-dichloroethane (30.0 mL) and DMF (8.0 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added N,O-dimethylhydroxylamine hydrochloride (0.535 g, 5.52 mmol) and triethylamine (1.15 mL, 8.28 mmol) and stirred at room temperature for 12 hours. The reaction was diluted with dichloromethane (20.0 mL) and washed with water, 0.5N HCl and saturated NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (1.0 g, 81% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.Cl.[CH3:30][N:31]([CH3:38])[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][N:31]([CH3:38])[C:32]([CH:34]1[CH2:37][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:35]1)=[O:33]
Reactant: CN(C)C(=O)C1CNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 62.8 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidine-3-carboxylic acid dimethylamide hydrochloride salt (53 mg, 0.32 mmol) in DCE (4 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 363 as a white solid (83 mg, 64%). LCMS (Method G): RT=5.23 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.70 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 9 H); 3.69-3.62 (m, 2 H); 3.57-3.46 (m, 3 H); 2.96 (s, 3 H); 2.93 (s, 3 H) and 2.90 (s, 3 H)
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:16])([F:15])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.OO.Cl>CO>[F:3][C:4]([F:15])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:1])=[O:12])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(OCC(F)(F)F)cc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)F)cc1
Temperature: 65 °C
Yield: 91 %

Procedure:
To a stirred solution of 50% w/v KOH (1.2 ml) and 4-(2,2,2-trifluoroethoxy)-benzaldehyde (0.6 g, 2.94 mmol) in MeOH (5 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 2.4 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×30 ml). The combined organic extracts were washed with brine (20 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (0.59 g, 91%) as a pale yellow solid which was used without further purification.
Reaction SMILES: Cl.C[O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH2:9][NH2:10].C([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1)=[NH:28])(OC(C)(C)C)=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65].O[Li].O>C(N(CC)CC)C>[F:67][C:66]([F:69])([F:68])[C:64]([OH:70])=[O:65].[CH3:15][CH:14]([CH3:16])[CH2:13][C:12]([NH:11][C@@H:6]([CH2:7][CH2:8][CH2:9][NH:10][C:36](=[O:37])[CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[NH:26])[NH2:28])=[CH:34][CH:33]=1)[CH2:5][C:4]([OH:3])=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CC(=O)O)cc1
Reactant: COC(=O)C[C@H](CCCN)NC(=O)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)CC(=O)N[C@@H](CCCNC(=O)Cc1ccc(C(=N)N)cc1)CC(=O)O

Procedure:
560 mg of the product of stage A) of example 2 is dissolved in 20 ml of methanol and hydrogenated in the presence of 0.3 g of Pd/C (10%) and 1.41 ml of 1N hydrochloric acid. After working up as described in stage C) of example 1, (S)-3-[N-(3-methylbutyryl)amino]-6-aminohexanoic acid methylester hydrochloride is obtained in the form of a colourless oil. 400 mg of the hydrochloride and 392 mg of N-Boc-p-amidinophenylacetic acid, together with 0.2 ml of triethylamine, 259 mg of HOBT and 290 mg of DCC, are reacted and worked up as described in stage C) of example 1. After cleavage of the Boc group with TFA and hydrolysis of the methylester with LiOH-H2O analogously to stage C) of example 1, the crude product obtained is recrystallized from methanol. The (S)-3-[N-(3-methylbutyryl)amino]-6-[N-(p-amidinophenylacetyl)amino]hexanoic acid trifluoroacetate product is isolated as a white powder; MS: 391 (M+H)+. The free compound is obtained from the trifluoroacetate in known manner.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(OC([N:29]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:41]([N:29]1[C:3]2[C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc3ccccc3c2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.4 %

Procedure:
A solution of (1 S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 240 mg, 1.12 mmol) in 1,2-dichloroethane (8 mL) was added to a cooled (0° C.) solution of triethylamine (210 μL, 1.5 mmol) and N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 37; 260 mg, 0.75 mmol) in 1,2-dichloroethane (4 mL) over 1 min. The reaction mixture was stirred at room temperature for 15 min, and then in an oil bath at 50° C. for 30 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the reaction mixture was heated at reflux for 1 h, and allowed to cool. Silica gel was added and the solvent was evaporated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was co-evaporated with diethyl ether and dried under high vacuum to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (93 mg, 30%) as an off-white solid. ES(+)-MS (M+H) 409.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9](O)=[N:8][C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]2=3)[CH2:3][CH2:2]1.P(Br)(Br)([Br:19])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Br:19][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1c(O)nc2cccnc2n1CC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1c(Br)nc2cccnc2n1CC1CC1
Yield: 66.5 %

Procedure:
700 mg (3.22 mM) of 4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one and 972.3 mg (3.22 mM) of phosphorus oxybromide at 95% in 10 ml of dichloroethane were refluxed for 16H under stirring. The reaction mixture was then basified with an aqueous solution of sodium carbonate and the aqueous layer was extracted with dichloromethane. The organic layer was separated, washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give, after evaporation, 650 mg of 2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one as a white solid. Yield: 66.5%.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (0.500 g, 1.40 mmol; Preparation #B.1) in DMF (15 mL) was cooled to about 0° C. and then treated with 60 wt % NaH (0.112 g, 2.80 mmol). The mixture was stirred for about 15 min at about 0° C. followed by the addition of SEMCl (0.372 mL, 2.10 mmol). The mixture was warmed to rt for about 15 min then was concentrated under reduced pressure and purified on a 40 g silica gel column eluting with DCM to provide 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.61 g, 89%): LC/MS (Table 2, Method b) Rt=3.88 min; MS m/z 487 (M+H)+.
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[S:13])SC)([OH:5])(=[O:4])=[O:3].[N-:14]=[N+:15]=[N-:16].[Na+]>>[S:2]([CH2:6][CH2:7][CH2:8][N:9]1[C:10]([SH:13])=[N:16][N:15]=[N:14]1)([OH:5])(=[O:4])=[O:3]
Reactant: CSC(=S)NCCCS(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [K]
Agent: [Na+]
Product: O=S(=O)(O)CCCn1nnnc1S

Procedure:
Reaction of methyl 3-sulfopropyldithiocarbamate potassium salt with sodium azide as described in Example 7 gave 1-(3-sulfopropyl)tetrazole-5-thiol.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Si]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:8][C:3]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([OH:16])=[CH:18][CH:19]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
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: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.38 g) was added to a suspension of 3-bromopyridin-2-amine (20.6 g), 4-(tert-butyldimethylsilyloxy)phenylboronic acid (39.0 g) and sodium carbonate (25.2 g) in DME (650 mL) and water (130 mL) and the mixture was stirred at 100° C. under nitrogen 6 hr. Volatiles were removed in vacuo, water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give 4-(2-aminopyridin-3-yl)phenol (7.90 g) as yellow crystals. The filtrate of crystallization was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyridin-2-amine (23.4 g) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[C:18]2[C:10]([C:11](=[O:20])[CH2:12][C:13]3([O:17]2)[CH2:16][CH2:15][CH2:14]3)=[C:9]([OH:21])[CH:8]=1)(=O)=O.[Cl-].[Li+].[Br-].[CH:27]1([Zn+])[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>O.Cl.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH:27]1([C:7]2[CH:19]=[C:18]3[C:10]([C:11](=[O:20])[CH2:12][C:13]4([O:17]3)[CH2:16][CH2:15][CH2:14]4)=[C:9]([OH:21])[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CC2(CCC2)Oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c21
Reactant: [Zn+]C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(CCC2)Oc2cc(C3CCCC3)cc(O)c21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 8.45 g (24.0 mmol) of 5-hydroxy-4-oxo-3,4-dihydrospiro[chromen-2,1′-cyclobutan]-7-yl trifluoromethanesulfonate (Example 44A), 3.92 g (4.8 mmol) of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and 6.10 g (144.0 mmol) of lithium chloride are suspended in 250 ml of abs. dimethylformamide. The mixture is cooled to 0° C., 216 ml (108 mmol) of (cyclopentyl)zinc bromide (0.5 M solution in tetrahydrofuran) are added and the mixture is stirred at room temperature overnight. Saturated ammonium chloride solution is then added to the mixture. The mixture is diluted with water, 1 N hydrochloric acid and ethyl acetate, the organic phase is separated off and the aqueous phase is extracted repeatedly with ethyl actate. The combined organic phases are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is adsorbed on silica gel and purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1). This gives 6.2 g (94% of theory) of the title compound in a purity of 90%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[CH3:45][S:46]([CH3:48])=O>>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:33][CH2:45][S:46][CH3:48])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of (2) (1.84 g, 3.7 mmol) in dry DMSO (7 ml) was added acetic acid (3.2 ml) and acetic anhydride (10.2 ml). The mixture was stirred for 2 days at room temperature, before it was quenched with sat. aq. NaHCO3. EtOAc (50 ml) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat. aq. NaHCO3 solution and dried (MgSO4). After removing the solvent under reduced pressure, the product (3) was purified by chromatography on silica (EtOAc:petroleum ether 8:2) yielding a clear sticky oil (1.83 g, 89%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.96-2.06 (m, 1H, H-2′), 1.99 (s, 3H, SCH3), 2.20-2.26 (m, 1H, H-2′), 3.63-3.74 (m, 2H, H-5′), 3.92-3.95 (m, 1H, H-4′), 4.11-4.13 (m, 2H, CH2), 4.28-4.30 (m, 1H, H-3′), 4.59 (br s, 2H, CH2), 5.97 (t, J=6.9 Hz, 1H, H-1′), 7.85 (s, 1H, H-6), 9.95 (t, J=5.3 Hz, 1H, NH), 11.64 (s, 1H, NH). Mass (−ve electrospray) calcd for C22H32F3N3O6SSi 551.17. found 550.