Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14]Br)[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]1([CH3:28])C=C[CH:25]=[CH:24][CH:23]=1.C[N:30](C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:30]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH3:28])[CH:6]=[CH:5]2
Reactant: Cc1ccccc1
Reactant: BrCCOc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CCCN1CCOc1ccc2cc(Br)ccc2c1
Temperature: 50 °C

Procedure:
The product from Example 37A (495 mg, 1.5 mmol), potassium carbonate (207 mg, 1.5 mmol), and the above toluene solution were suspended into DMF (3 mL) and heated at 50° C. overnight. The reaction mixture was brought to room temperature and partitioned between 0.2 M aqueous NaOH (20 mL) and dichloromethane (10 mL). The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed with 0.2 M aqueous NaOH, dried (Na2SO4), and filtered quickly through a silica plug with a 0 to 10% methanol/dichloromethane gradient. The filtrate was partitioned between water and 2:1 dichloromethane/hexanes. The aqueous phase was separated and extracted with 20% hexanes/dichloromethane, and the combined organic phases were concentrated and chromatographed through silica with a little hexanes/dichloromethane followed by a gradient of 0 to 10% methanol/dichloromethane. The appropriate fractions were combined and concentrated under high vacuum to provide 451 mg of a 6:1 mixture of title compound and starting dibromide which was used in the next step without further purification; MS (ESI APCl) m/z 334/336 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]([NH2:9])=[O:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of compound (1b) in DMSO (4.41 mL) were added 4N aqueous sodium hydroxide solution (160 μL) and 30% aqueous hydrogen peroxide solution (60 μL), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, water was poured into the reaction solution, and the precipitated solid was collected by filtration to obtain compound (1) (150 mg, yield 96%) as a white solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39]([C:40]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=O)=[CH:38][C:37]=2[O:36]1>O1CCCC1.O>[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39](/[C:40](/[C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:38][C:37]=2[O:36]1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cccnc1)c1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCC/C=C(\c1cccnc1)c1ccc2c(c1)OCO2
Temperature: 85 °C
Yield: 11.2 %

Procedure:
Sodium hydride (1 g, 60% in oil) was added to dimethyl sulfoxide (25 ml) under nitrogen and the mixture was heated at 85° C. with stirring for an hour. The reaction mixture was cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (5.2 g, 11 mmoles) was added gradually. The mixture was stirred for 10 minutes and a solution of 3-(3,4-methylenedioxybenzoyl)pyridine (2.5 g, 0.11 mole) in tetrahydrofuran (10 ml) was added dropwise thereto. After completion of addition, the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, water (100 ml was added and the neutral substance was extracted twice with toluene (50 ml). The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the eluent. The eluate was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (Z)-7-(3,4-methylenedioxyphenyl)-7-(3-pyridyl)-6-heptenoic acid (0.4 g, 24.6%). Mp 90°-91° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N+:37]([O-])=O)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:26]([C:10]1[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])[CH2:36]2
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 87.7 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl)methanone (460 mg; 0.88 mmol) in ethanol (25 ml) was treated with tin (II) chloride dihydrate (1 g; 5 equiv.) then heated at reflux overnight then evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, the EtOAc layer was separated, dried (MgSO4) and evaporated to give 380 mg of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:1]([NH:5][S:6](/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)CC(O)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)NS(=O)(=O)/C=C/c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
A mixture of N-tert-butyl-2-hydroxy-2-(4-pyridyl)ethane-sulfonamide (6.62 g), acetic anhydride (13.2 ml) and pyridine (26.4 ml) was stirred at room temperature for 1.5 hr. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.58 ml), and the mixture was stirred in an oil bath at 100° C. for 40 min. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated brine. Th aqueous layer was extracted with ethyl acetate and organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give (E)-N-tert-butyl-2-(4-pyridyl)ethenesulfonamide (3.91 g) as a pale-yellow solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[NH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.CCN(C(C)C)[CH:15]([CH3:17])[CH3:16]>C(Cl)Cl>[CH2:1]([N:5]([CH2:17][CH:15]=[CH2:16])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH:2]=[CH2:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1cccs1
Reactant: C=CCBr
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1cccs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 801.5 %

Procedure:
Allyl bromide (55 ml, 65.4 mmol) is added to a solution of 2-aminomethyl-thiophene (24 ml, 23.3 mmole) and i-Pr2NEt (120 ml, 70.1 mmol) in CH2Cl2 (270 ml). The moderately exothermic reaction spontaneously reaches the reflux temperature after 1 h. The reaction is cooled by means of an ice bath and stirred for 14 h at rt. whereupon an undesired precipitate appeared. This precipitate (45 g) is removed by filtration. The organic layer is evaporated and diluted with EtOAc, whereupon more precipitate appears (45 g), which is removed by filtration. The EtOAc solution is filtered over SiO2 and concentrated to give 36.1 g (80%) of the title diallylamine as a pale yellow oil: 1H NMR (CDCl3) δ 7.25 (br. d, J=5.9 Hz, 1H), 6.98 (br. dd, J=5.1, 2.8 Hz, 1H), 6.94-6.92 (m, 1H), 5.99-5.86 (m, 2H), 5.29-5.18 (m, 4H), 3.85 (s, 2H), 3.16 (dd, J=6.3, 0.9 Hz, 4H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]([S:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O:28]CC)C>O1CCCC1>[CH2:10]([S:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)=[O:28])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: Fc1ccc(Br)cc1
Reactant: N#Cc1ccc(SCc2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1ccc(SCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 9.6 g of magnesium turnings in 20 ml of anhydrous diethyl ether is added dropwise a solution of 44 ml of 4-bromo-1-fluorobenzene in 300 ml of anhydrous diethyl ether. At the end of the addition, the mixture is stirred for a few minutes at room temperature and a solution of 46 g of 4-benzylthiobenzonitrile, prepared in example 16, in 400 ml of anhydrous tetrahydrofuran is added dropwise. The diethyl ether is distilled off and the mixture is heated under reflux for 3 hours before being cooled with ice. A 6 M solution of hydrochloric acid (400 ml) is added dropwise and the mixture is heated under reflux for 6 hours. After the addition of water and dichloromethane, the organic phase is separated, dried over magnesium sulphate and evaporated in vacuo. The residue crystallises in diisopropyl ether to give 48 g of 4-benzylthio-4'-fluorobenzophenone as crystals with a melting point of 96° C.
Reaction SMILES: CC(C)CC([OH:6])C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[P:22](=[S:26])([OH:25])([OH:24])[SH:23].[O-2].[Zn+2:28]>O.C(O)(C)C>[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[Zn+2:28].[O-2:6].[Zn+2:28]
Reactant: OP(O)(=S)S
Reactant: CC(C)CC(C)O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: [O-]P([O-])(=S)[S-]
Reaction time: 4 h

Procedure:
Preparation 1. A mixture of 12 mole percent isopropanol and 88 mole percent 4-methyl-2-pentanol is reacted with phosphorus pentasulfide in approximately a 4.5:1 molar ratio at a maximum temperature of 80° C. The resulting dithiophosphoric acid mixture is reacted with a 12% molar excess of zinc oxide suspended in mineral oil at a temperature of 90° C. for four hours. After the reaction is complete, water of reaction and excess alcohols are distilled under a reduced pressure of 2.7 kPa (20 mm Hg) at 90° C. The product, containing about 9 percent by weight diluent oil, has a Total Base Number (TBN, ASTM D-2896) of 5.56 and includes about 14 percent basic zinc dithiophosphate by 31p NMR analysis. The product contains 8.70% P and 9.45% Zn. (The basic zinc salt is a known material which is formed during the zinc oxide reaction, from 3 moles of neutral zinc dithiophosphate and one mole of zinc oxide. The basic zinc salt is believed to be in the form of a tetrahedral complex that titrates with strong mineral acid, and it is believed to account for the TBN content of the product mixture.)
Reaction SMILES: Cl.C([O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][N:9]([CH2:17][CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)C>O1CCOCC1.O>[CH2:17]([N:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:19])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[CH3:18]
Reactant: CCOC(=O)CCCN(CC)c1cccc(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCN(CCCC(=O)O)c1cccc(C)c1
Temperature: 95 °C
Reaction time: 12 h
Yield: 109.5 %

Procedure:
4N Solution (100 ml) of hydrogen chloride in dioxane and water (20 ml) was added to the compound (14.1 g) obtained in Step 1, and the mixture was stirred at 95° C. for 12 hours. The solvent was evaporated to give the title compound (13.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: COc1ccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(C)c(OCCN4CCCC4)c(C)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one (1.94 g, 4.80 mmol) in N,N-dimethylformamide (20 mL), pyrrolidine (4 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was washed with ether to give the title compound as a light brown solid. Yield: 0.30 g (16%). MP 201.2-203.1° C. 1H NMR (400 MHz, CDCl3): δ 7.73 (m, 4H), 7.39 (m, 1H), 3.98 (t, J=6.0 Hz, 3H), 3.94 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.69 (br s, 4H), 2.41 (s, 6H), 1.86 (br s, 4H). MS (ES) m/z: 394.21 (M++1).
Reaction SMILES: Br.[CH2:2]([N:9]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([OH:32])[CH:26]=1)=[O:24])[CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:33]([OH:38])(=O)[CH2:34][CH2:35][CH3:36].Cl.[C:40]([Cl:45])(=[O:44])[CH2:41][CH2:42][CH3:43]>>[ClH:45].[CH2:2]([N:9]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])=[C:27]([O:32][C:33](=[O:38])[CH2:34][CH2:35][CH3:36])[CH:26]=1)=[O:24])[CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC(=O)Cl
Reactant: O=C(Cc1ccccc1)NCCN(CC(=O)c1ccc(O)c(O)c1)Cc1ccccc1
Reactant: CCCC(=O)O
Agent: Br
Agent: Cl
Product: CCCC(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)CCC
Reaction time: 1.5 h

Procedure:
A mixture of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-dihydroxyacetophenone hydrobromide (1.0 g.) and butyric acid (6 ml.) was saturated at room temperature with gaseous hydrogen chloride during 3 minutes. Butyryl chloride (6 ml.) was then added and the mixture was stirred at 90°-95° C. for 1.5 hours, giving a clear solution after about 5 minutes. The solution was then concentrated to half volume by evaporation under reduced pressure and the residue was diluted with ether (25 ml.) to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(butyryloxy)acetophenone hydrochloride as a solid precipitate (0.65 g.), m.p. 115°-117° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:44]([NH:43][CH2:42][C@@H:40]1[O:39][C:38](=[O:47])[N:37]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:36])[CH2:35][CH2:34][CH2:33][N:32]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:31][CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:41]1)(=[O:46])[CH3:45]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7 with 98 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.348 mmol), 138 mg N-{(5S)-3-[3-fluoro-4-(4-hydroxy-azepan-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (MW: 395.43, 0.348 mmol), 140 mg triethylamine (MW: 101.19, 1.39 mmol) and 113 mg trimethylchlorsilan (MW: 108.64, 1.04 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 150 mg, 77%. MS: 642.7 (M+H)+, 640.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([OH:13])(=[O:12])[CH3:11].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([OH:56])[CH2:26][N:27]([CH2:43][C@H:44]([OH:55])[C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([NH:52][CH:53]=[O:54])[CH:46]=2)[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[CH:34][CH:33]=2)=[CH:21][C:20]=1[NH:57][CH:58]=[O:59].I.[NH2:61][C:62]1[C:63]([C:70]([NH:72][C:73](=[NH:76])SC)=[O:71])=[N:64][C:65]([Cl:69])=[C:66]([NH2:68])[N:67]=1>C(O)C>[C:10]([OH:13])(=[O:12])[CH3:11].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:55][C@H:44]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([NH:52][CH:53]=[O:54])[CH:46]=1)[CH2:43][N:27]([CH2:26][C@@H:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[C:20]([NH:57][CH:58]=[O:59])[CH:21]=1)[OH:56])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:73]([NH:72][C:70]([C:63]2[C:62]([NH2:61])=[N:67][C:66]([NH2:68])=[C:65]([Cl:69])[N:64]=2)=[O:71])=[NH:76])=[CH:36][CH:37]=1
Reactant: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.92 mmol) was added to a solution of {4-[4-(4-{bis-[2-(4-hydroxy-3-formylaminophenyl)-2-(R)-hydroxyethyl]amino}-butyl)phenyl]butyl}amine diacetic acid salt (13) (129 mg, 019 mmol) in absolute ethanol (4 mL). The mixture was stirred at 70° C. (oil bath) for 10 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (79 mg, 0.20 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and cooled to rt. The solvent was removed by rotary evaporation. The residue was purified by Biotage silica gel column chromatography (A=dichloromethane, B=10% concentrated aqueous ammonium hydroxide in methanol, gradient B/A 1% to 25%) to give the desired adduct 14 as a greenish yellow solid (44 mg, 26%): 1H NMR (500 MHz, DMSO-d6) δ 1.50 (m, 8H), 1.98 (s, 6H), 2.58 (m, 4H), 3.20 (m, 8H), 4.45 (m, 2H), 6.60 (br, 2H), 6.80 (m, 4H), 7.08 (m, 4H), 8.00 (s, 2H), 8.28 (s, 2H), 9.56 (br, 2H); m/z (ESI) 791 [C38H47ClN10O7+H]+; [α]D25 −4.0° (c 0.35, MeOH); mp 128-130° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 4,4-dimethylpentylamine (0.194 g, 1.68 mmol) (Example 97, Part B) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give the title compound (0.314 g, 57%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H26N4O2F 361.2040 (M+H)+, found 361.2042, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.0 min. 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Br[Si](C)(C)C>C1(=O)OC(C)CO1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Solvent: CC1COC(=O)O1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 97 %

Procedure:
As in Example 1, 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) was silylated and the toluene was distilled off to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (16.21 g) and bromotrimethylsilane (3.11 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 8 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 1 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (27.90 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:2]1.C1(=C/C2C=CC=CN=2)/CCC2C/1=CC=CC=2.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:59].[Cl-].[Cl-].[Cr+3:62]>O1CCCC1>[Cl-:59].[Cl-:59].[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[Cr+2:62]
Reactant: C1=C(Cc2ccccn2)c2ccccc2C1
Reactant: [Cr+3]
Agent: C(=C1\CCc2ccccc21)\c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Cr+2]C1=Cc2ccccc2C1Cc1ccccn1
Temperature: -100 °C
Reaction time: 0.75 h

Procedure:
A solution of 52.7 g of the above mixture of 2-(1H-inden-3-ylmethyl)pyridine and 2-[(E)-2,3-dihydro-1H-inden-1-ylidenemethyl]pyridine in a molar ratio of 10:9 in 550 ml of tetrahydrofuran was cooled to −100° C. 80.5 ml of a 15% strength n-butyllithium solution in hexane (0.1288 mol) were then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further 45 minutes. The mixture was subsequently allowed to warm to room temperature. After stirring for a further 2 hours, the solution was cooled to 60° C. and 49 g (0.1288 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred for a further 10 hours at room temperature. The reaction mixture was then refluxed for 20 minutes and subsequently cooled to room temperature. The solid which had precipitated was filtered off and washed with hot tetrahydrofuran. The solid was subsequently washed with diethyl ether and dried under reduced pressure. This gave 24.9 g of (1-(2-pyridylmethyl)indenyl)chromium dichloride (59%).