Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]([C:5]1[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=1)=[O:4].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)C>[C:12]1([NH:18][NH:19][C:3]([C:5]2[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=2)=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSC(=O)c1nc(Cl)c(Cl)[nH]1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(NNc1ccccc1)c1nc(Cl)c(Cl)[nH]1
Yield: 49.8 %

Procedure:
21.1 g (0.1 mol) of 4,5-dichloro-imidazole-2-thiocarboxylic acid S-methyl ester were boiled with 10.8 g (0.1 mol) of phenylhydrazine in 150 ml of ethanol for 4 hours under reflux. The cooled reaction mixture was mixed with 500 ml of water and the crystals which had separated out were filtered off and dried. 13.5 g (50% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid N'-phenyl-hydrazide with a melting point of 229°-230° C. (from ethyl acetate) were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]([NH2:20])(=[O:19])[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([NH:20][C:17](=[O:19])[CH3:18])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cc(Cl)cc(N2CCOCC2)c1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(N2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure V using palladium (II) acetate (0.013 g, 0.057 mmol), tetramethyl t-butyl XPhos (0.082 g, 0.170 mmol), 4-(3-chloro-5-nitrophenyl)morpholine (0.275 g, 1.133 mmol), acetamide (0.080 g, 1.360 mmol), tripotassium phosphate (0.337 g, 1.587 mmol), and tert-butanol (2.5 mL) to afford N-(3-morpholino-5-nitrophenyl)acetamide. No purification was performed. Mass Spectrum (ESI) m/e=266.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13](Cl)=[O:14].[OH-].[NH4+:17]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:17])=[O:14]
Reactant: O=C(Cl)/C=C1\CCc2c(Cl)cc(F)cc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
A solution of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetyl chloride (4.0 g, 0.015 mol) [as prepared in example 1 g] in dichloromethane (36 ml) was added dropwise to an ice-cold mixture of 30% aqueous ammonium hydroxide (2.0 ml, 0.03 mol) and dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate solution was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate:hexanes (2:1) as eluent. Trituration of the resulting solid with pentane gave 1.47 g (43%) of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetamide as a white solid: m.p. 182°-184° C.
Reaction SMILES: [Mg].[CH3:2][C:3]1[S:7][CH:6]=[C:5](/[CH:8]=[C:9](/[C@H:11]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19]([CH3:35])[CH2:18][CH2:17][CH2:16][C@H:14]3O[C@H:13]3[CH2:12]2)\[CH3:10])[N:4]=1>[Cl-].[Cl-].C1([Ti+2]C2C=CC=C2)C=CC=C1.C1COCC1>[CH3:2][C:3]1[S:7][CH:6]=[C:5](/[CH:8]=[C:9](/[C@H:11]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19]([CH3:35])[CH2:18][CH2:17][CH2:16][CH:14]=[CH:13][CH2:12]2)\[CH3:10])[N:4]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a two-necked flask was added chopped pieces of magnesium turnings (24 mg, 1.0 mmol). The flask was flame-dried under vacuum and cooled under argon. Bis(cyclopentadienyl)titanium dichloride (250 mg, 1.0 mmol) was added followed by anhydrous THF (5 mL). The stirring suspension was evacuated with low vacuum, and the reaction flask was refilled with argon. The red suspension became dark, turning a homogeneous deep green after 1.5 h with nearly all the magnesium metal being consumed. An aliquot (3.5 mL, 0.70 mmol, 3.5 eq) was removed and cooled to −78° C. under argon. To this solution was added epothilone A (99 mg, 0.20 mmol, 1.0 eq). The reaction mixture was warmed to room temperature and stirred for 15 min. The volatiles were removed in vacuo and the residue was chromatographed two times on silica (25 g), eluting with 35% EtOAc/hexanes to give 76 mg (80%) of epothilone C as a pale yellow viscous oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>CS(C)=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: OCCNCCO
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N(CCO)CCO
Temperature: 140 °C
Yield: 83.9 %

Procedure:
In 30 ml of DMSO, 4.0 g (25.8 mmol) of 2-fluoro-5-nitrotoluene and 7.0 g (67 mmol) of diethanolamine were dissolved. The resultant solution was stirred under heat at 140° C. for 6.5 hours, followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure. The residue so obtained was washed with ethyl acetate, whereby 5.2 g of the title compound were obtained as yellow powder (yield: 84%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[CH3:23])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[CH3:23])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25])=[N+:28]=[N-:29]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
A mixture of 0.7 g (1.9 mmol) of 7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile and 0.62 g (9.5 mmol) of sodium azide is heated at 60° C. under nitrogen for 24 hours. The mixture is cooled and poured onto ice. The solid is collected by filtration, washed with water and dried to yield 0.65 g of 7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile as a yellow solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[NH3:13]>>[SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([NH2:13])=[O:10]
Reactant: N
Reactant: O=C(O)CCCC(=O)NCCS
Product: NC(=O)CCCC(=O)NCCS

Procedure:
A solution of 9.1 g (44 mmol) of methyl ester of N-(2-mercaptoethyl)glutaramic acid obtained in Example 4a), in 100 cm3 of aqueous 20% solution of aqueous ammonia was stirred for 4 hours at ambient temperature under argon atmosphere. After evaporation to dryness and recrystallization from isopropanol 7 g of N-(2-mercaptoethyl)glutaramide were obtained in the form of a white solid with a melting point of 127° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[N:11])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].BrBr.[NH2:14][C:15](=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>Cl.C(O)(=O)C.CCO>[C:10]([C:6]1[CH:5]=[C:4]([C:1]2[N:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:21][CH:2]=2)[CH:9]=[CH:8][CH:7]=1)#[N:11]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCOC(=O)C(N)=S
Agent: BrBr
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2cccc(C#N)c2)cs1

Procedure:
At room temperature, 10 drops of a conc. aqueous hydrogen chloride solution are added to 5.00 g (34.4 mmol) of 3-acetylbenzenecarbonitrile in 40 ml of conc. acetic acid. 1.8 ml (34.4 mmol) of bromine in 10 ml of conc. acetic acid are subsequently added dropwise over a period of 1 h, and after the end of the addition, the reaction mixture is poured onto ice. After extraction of the aqueous phase with dichloromethane, the combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The solid obtained (8.00 g) is provided in 250 ml of EtOH and heated under reflux, a solution of 3.77 g (28.3 mmol) of ethyl amino(thioxo)acetate in 50 ml of ethanol is added dropwise and the mixture is stirred under reflux for 3 h. The reaction solution is cooled and the precipitate formed is collected by filtration. The mother liquor is concentrated under reduced pressure, the residue is taken up in a little ethanol and the solid formed is subsequently collected by filtration. 5.75 g (65% of theory) of the title compound are obtained after combining the solids.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:43])/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1(/[CH:36]=[CH:35]/[C:34]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)/C=C/c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added trans-cinnamoyl chloride (0.235 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave a yellow syrup that was crystallized from diethyl ether/ethyl acetate/hexane to afford the title compound (0.360 g, 85%) as an off-white solid, m.p. 175° C.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=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>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)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+]
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Using tert-butyl {{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (1 g), phenylboronic acid (526 mg), sodium carbonate (687 mg) and tetrakis(triphenylphosphine)palladium (374 mg), a procedure as in Reference Example 57 was performed to give the title compound as a pale-yellow oil (yield 726 mg, 73%).
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2]>C1C=CC=CC=1>[CH:1]([C:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)=[CH2:2]
Reactant: C=CC1(O)CCCCCCC1
Solvent: c1ccccc1
Product: C=CC1=CCCCCCC1
Yield: 67 %

Procedure:
A solution of 6 grams of 1-vinylcyclooctanol and 50 mg of MTO in 30 ml of benzene was refluxed 18 hours, cooled, washed with aq. potassium carbonate, dried, stripped of solvent and distilled (82-85 deg C./25 mm Hg) to give 3.55 grams of 1-vinylcyclooctene judged to be of 95% purity of NMR analysis; the only impurity was cyclooctanone left over from preparation of the vinyl carbinol.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])[C:3]1=[O:20]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-methyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 274°-277° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(OC(=O)C)(=O)C>[C:16]([O:19][CH2:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2[nH]c(=O)c(CCl)cc2c1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]c(=O)c(COC(C)=O)cc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.2 Grams of 3-chloromethyl-6-methoxycarbostyril was dissolved in 20 ml of acetic anhydride, then 12 g of potassium acetate was added thereto and stirred at 60°-70° C. for 3 hours. The reaction mixture was poured in an ice-water and the crystals precipitated were collected by filtration. Recrystallized from acetone to obtain 2 g of 3-acetoxymethyl-6-methoxycarbostyril in the form of colorless prism-like crystals.
Reaction SMILES: [Cl-].[Ti+4:2].[Cl-].[Cl-].[Cl-].Cl.ClCl.[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12]>O.CCCCCC>[CH3:12][CH2:11][CH2:10][CH2:9][O-:13].[CH3:12][CH2:11][CH2:10][CH2:9][O-:13].[CH3:12][CH2:11][CH2:10][CH2:9][O-:13].[CH3:12][CH2:11][CH2:10][CH2:9][O-:13].[Ti+4:2]
Reactant: CCCCO
Agent: [Ti+4]
Agent: Cl
Agent: ClCl
Solvent: O
Solvent: CCCCCC
Product: CCCC[O-]
Temperature: 30 °C
Reaction time: 2 h

Procedure:
The reaction apparatus consisted of a heated enameled vessel of two cubic meters capacity, equipped with three feed tubes, a stirrer, and a glass condenser operated with water and connected to a 4 square meter Hastelloy C brine cooler (-45° C.). 670 liters of hexane were placed in it and refluxed. The temperature below the water condenser amounted to 69° C. Over a period of 2 hours 380 kg of titanium chloride (2 kmol) and 444 kg of n-butanol (6 kmol) were put in at such a rate that the molar ratio of titanium chloride to n-butanol amounted always to about 1:3. Immediately at the start of the addition a vigorous evolution of hydrogen chloride began. The temperature below the water condenser dropped to 60° C. and rose toward the end of the reaction back to 64° C. After the reaction another 155.4 kg of n-butanol (2.1 kmol) was added with stirring. A sample had a chlorine content of 11.6%. This meant that 47.5% of the chlorine present had been removed in the form of hydrogen chloride. After cooling to about 30° C., the mixture was first diluted with 200 liters of hexane, and then ammonia was fed through the third feed tube for a period of 2 hours. The suspension obtained was centrifuged to separate the precipitated ammonium chloride. First the hexane was distilled out of the filtrate; then, at a vacuum of less than 1 mbar and at a head temperature of about 155° C., the butyl titanate was purified by distillation. 619 kg of butyl titanate was obtained.
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C([C@@H]([C@H](CO)OCP(O)(O)=O)O)=O)C=N2)=NC=1.[N:25]1([C:34]([C@@H:36]([C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([O:47]C(C)C)([O:43]C(C)C)=[O:42])[OH:37])=[O:35])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:34]([C@@H:36]([C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([OH:43])([OH:47])=[O:42])[OH:37])=[O:35])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: Cc1cn(C(=O)[C@H](O)[C@H](CO)OCP(=O)(OC(C)C)OC(C)C)c(=O)[nH]c1=O
Agent: Nc1ncnc2c1ncn2C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O
Agent: [Na]
Product: Cc1cn(C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O)c(=O)[nH]c1=O
Yield: 42 %

Procedure:
This compound was prepared as described for 3a, using 16 (220 mg, 0.58 mmol) as starting material. Compound 3b (90 mg, 0.24 mmol) was obtained as a colorless solid in 42% yield, which was characterized as follows:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([F:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(F)c3)nc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(F)c4)c(F)c3)nc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a reaction vial was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-fluoropyridin-3-yl)acetamide 190-6 (66 mg, 0.17 mmol), 2-fluoropyridin-4-ylboronic acid 193-1 (35 mg, 0.25 mmol), Pd(OAc)2 (2 mg, 0.009 mmol), S-Phos (7 mg, 0.017 mmol) and K3PO4 (108 mg, 0.51 mmol) in 2-butanol (0.3 mL). The reaction was heated to 100° C. and stirred for 2 hours. The reaction was cooled down to room temperature and then diluted to DMSO. The reaction mixture was filtered and the filtrate was purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetamide 194. MS m/z 453.1 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][N:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 9) (0.27 g, 0.63 mmol, 1 eq), DIPEA (0.21 mL, 1.26 mmol, 2 eq) and TBTU (0.22 g, 0.69 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (91 μl, 0.75 mmol, 1.2 eq). The RM was then stirred at rt for 4 hours before washing with water, concentrating in vacuo and purifying the residue by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.14 g, 44%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([O:25]CC)=[O:24])=[N:6][CH:5]=1>C1COCC1.C(O)C.O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([OH:25])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Aqueous lithium hydroxide solution (1M, 44 mL, 44.00 mmol) was added to a solution of ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (9.14 g, 21.96 mmol) in THF (60 mL), ethanol (24 mL) and water (20 mL), and stirred for 4 h. After concentrating, the residue was acidified with aqueous HCl solution (1N, 50 mL), diluted with water (100 mL) and filtered to afford 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid as an off-white solid (8.52 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: FC(F)(F)CN1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(4-bromophenyl)piperazine (1.24 g, 5.16 mmol) in DCM were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.20 mL, 7.22 mmol) and cesium carbonate (5.04 g, 15.0 mmol). The resulting mixture was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was collected and concentrated in vacuo. Purification by chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 324.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J=9.1 Hz, 2 H),6.78 (d, J=9.0 Hz, 2 H),3.19-3.16 (m, 4 H),3.03 (q, J=9.5 Hz, 2 H),2.84-2.81 (m, 4 H).