Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[N:26]=[C:25]([C@@:27](O)([CH3:42])[CH2:28][NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:24]([F:44])=[C:23]([Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:20][C:21]1[N:26]=[C:25]([C:27]2([CH3:42])[CH2:28][N@@:29]2[S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:24]([F:44])=[C:23]([Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH:22]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](C)(O)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triphenylphosphine (21.55 g, 82 mmol) and (R)—N-(2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-hydroxypropyl)-4-nitrobenzenesulfonamide (37.56 g, 69 mmol) in 510 ml THF was cooled to 4° C. A solution of diethyl azodicarboxylate in toluene (40% by weight, 38.8 g, 89 mmol) was added in a dropwise while maintaining the temperature below 10° C. The cooling bath was removed and the rm was stirred at rt for 1 h. The reaction mixture was diluted with approx. 1000 ml toluene and THF was removed by evaporation at the rotavap. The resulting toluene solution of crude product was pre-purified on a silca gel column by eluting with hexanes/5-17% EtOAc. Purest fractions were combined, evaporated and crystallized from TBME/hexane to yield 29.2 g of the title compound as white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:2]1.O.[NH2:16][NH2:17]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:11]=[C:12]([NH2:13])[NH:16][N:17]=2)=[CH:2]1
Reactant: NN
Reactant: N#CCC(=O)c1c[nH]c2ccccc12
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2c[nH]c3ccccc23)n[nH]1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of 3-(1H-indol-3-yl)-3-oxo-propionitrile (6.4 g, 34.7 mmol, 1.0 eq), in absolute EtOH (40 mL), hydrazine monohydrate (5.0 mL, 104.1 mmol, 3.0 eq) was added and the reaction was heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature; the solid was filtered and washed with Et2O/EtOAc 10/1 to give 3.0 g of title product (yield 74%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.NC1SC=CN=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:25][C:26]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCNc1nccs1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Nc1nccs1
Product: O=C(NC(=S)NCCCNc1nccs1)c1ccccc1

Procedure:
By the procedure of Example 46, reacting 2-(3-aminopropylamino)thiazole prepared from 2-aminothiazole by the method of Example 53)with benzoyl isothiocyanate gives N-benzoyl-N'-[3-(2-thiazolylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-thiazolylamino)propyl]thiourea.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][NH:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1.[CH2:12]=O>C(O)C.[Pd]>[CH3:12][N:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[O:3][CH2:4][CH:5]1[C:8]([OH:10])=[O:9]
Reactant: C=O
Reactant: CC1(C)CNC(C(=O)O)CO1
Agent: [Pd]
Solvent: CCO
Product: CN1CC(C)(C)OCC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a suspension of 6,6-dimethyl-morpholine-3-carboxylic acid (Intermediate 19, 540 mg) in 17 ml of ethanol (under nitrogen) was added 100 mg of 10% Pd on charcoal and 830 ul (3 eq.) of 37% aqueous formaldehyde. The mixture was purged with hydrogen (balloon) and stirred at ambient temperature for 5 hrs. To the resulting gray mixture were added 4 ml of water and 4 ml of methanol to help dissolution. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with EtOAc. The generated white solid was filtered off and dried under high vacuum to give 574 mg of 4,6,6-trimethyl-morpholine-3-carboxylic acid (97% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](I)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccsc1)=CCC2c1ccccc1
Yield: 90.9 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 30 cm3 of toluene, from 150 mg of tetrakis(triphenylphosphine)palladium, from 0.35 g of 3-thienylboronic acid in 15 cm3 of methanol and from 28 cm3 of a 2N aqueous sodium carbonate solution at reflux for three hours, 0.99 g (93%) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2ccc(=O)[nH]c12
Temperature: 25 °C
Yield: 53.6 %

Procedure:
Methyl bromoacetate (367 mg, 2.4 mmol) was added to a stirred mixture of 8-hydroxy-1H-quinolin-2-one [which was prepared according to literature procedure (Wang, T. C. et al, Synthesis, 1997, 87-90)], (322 mg, 2 mmol), K2CO3 (414 mg, 3 mmol) in DMF (10 ml) at room temperature. The reaction mixture was stirred at rt over night and then partitioned between dichloromethane and water. Water layer was extracted with dichloromethane (2×50 ml). The combined organic phase was washed with water (3×50 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was washed with ether to give 250 mg of compound I-71.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O>COCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:27]4[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=4)[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2CCN(C3=Nc4ccccc4Oc4ccc(Cl)cc43)CC2)nc1
Yield: 100.2 %

Procedure:
A solution of (E)-2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine (0.25 g, 0.8 mmol) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.13 g, 0.57 mmol) in DME was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous solution of bicarbonate, water, acetic acid and sodium acetate (pH=4), dried over sodium sulfate and solvent evaporated. The resulting crude residue was purified by flash chromatography (0% to 30% ethyl acetate in hexane) to afford title compound 116 (0.265 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:28]=2[N:29]=1.[OH-].[Na+].[CH2:38](O)CCC>>[F:35][C:30]1[C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]5[CH2:38][CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:12][CH:13]=4)=[CH:6][CH:7]=3)[S:26][C:27]=2[CH:33]=[C:32]([F:34])[CH:31]=1
Reactant: Fc1cc(F)c2nc(Cl)sc2c1
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCCCO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4c(F)cc(F)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of racemic methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutane-carboxylate (250 mg, 0.77 mmol) in n-butanol (15 mL) was added 2-chloro-4,6-difluoro-1,3-benzothiazole (318 mg, 1.55 mmol), and the resulting solution was heated at 90° C. overnight. The mixture was then evaporated to dryness under reduced pressure, and the residue was brought up in MeOH. Then 1 N aqueous NaOH (8.0 mL, 8.0 mmol) was added to the suspension, and the reaction mixture was stir-red at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Conc. HCl was added to adjust the acidity to pH 1, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was brought up in MeOH, and the precipitate was collected by filtration, washed with MeOH, EtOAc, and DCM, and dried in a vacuum oven to afford racemic trans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentanecarboxylic acid (160 mg, 43%). LC-MS ret. time 4.12; m/z 479.3 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.86 (m, 4H), 2.00 (m, 1H), 2.18 (m, 1H), 3.22 (q, 1H), 4.01 (q, 1H), 7.28 (m, 1H), 7.65 (m, 1H), 7.82 (m, 4H), 7.88 (d, 2H), 8.05 (d, 2H), 10.83 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21]C(=O)C)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([NH2:21])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1[nH]nc(-c2cccc(F)c2)c1C#Cc1ccccc1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
A mixture of N-[3-(3-fluorophenyl)-4-(2-phenylethynyl)-1H-pyrazol-5-yl]acetamide (2 g, 6.2 mmol), ethanol (22 mL) and 25% aq. NaOH solution (22 mL) was stirred and heated to 80° C. for 1 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo, to provide the title compound as a solid (1.2 g).
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>C1COCC1>[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:2])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A suspension of 34.1 g of methylriphenylphosphonium bromide in 400 mL of dry THF was treated with 10.7 g of potassium t-butoxide under a nitrogen atmosphere. After stirring for 10 min at room temperature, the yellow solution was treated with a solution of 21.2 g of p-t-butoxycarbonyloxybenzaldehyde in 100 mL of dry THF. After stirring for one hour, the mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC to yield 16.6 g (79%) of pure p-t-butoxycarbonyloxystyrene. Alternately, IIIc was purified by distillation under reduced pressure.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32](I)=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1)(=O)C1C=CC=CC=1.[NH2:56][CH2:57][CH2:58][NH:59][C:60]([NH:62][CH2:63][CH2:64][N:65]([CH:69]([CH3:71])[CH3:70])[CH:66]([CH3:68])[CH3:67])=[O:61].C1C[O:75][CH2:74]C1>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>[CH3:54][C:50]1[CH:49]=[C:48]([CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:74]([NH:56][CH2:57][CH2:58][NH:59][C:60]([NH:62][CH2:63][CH2:64][N:65]([CH:69]([CH3:71])[CH3:70])[CH:66]([CH3:67])[CH3:68])=[O:61])=[O:75])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@H:11]2[C@H:10]([OH:9])[C@H:14]([OH:15])[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12]2)[CH:53]=[CH:52][CH:51]=1
Reactant: C1CCOC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)N(CCNC(=O)NCCN)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(C(=O)NCCNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Reaction time: 14 h

Procedure:
A solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-{[2,2-bis(3-methylphenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 48) (200 mg, 0.24 mmol), N-(2-aminoethyl)-N′-[2-(diisopropylamino)ethyl]urea (Preparation 52) (270 mg, 1.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.024 mmol) in THF (5 ml) was carbonylated at 60° C. and 345 KPa under a carbon monoxide atmosphere for 14 hours. TLC analysis showed the desired product together with partially deprotected material. To achieve complete removal of the benzoate protecting groups, solvent was evaporated under reduced pressure, the residue dissolved in methanol (10 ml), sodium carbonate (10 mg) added and the mixture allowed to stir at room temperature for 24 hours. Solvent was again evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (90:10, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (90:10:1, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.11 g, 61%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(Cl)cc13)CCCNC2=O

Procedure:
The title compound, white solid (71 mg, 79%), MS (ISP) m/z=361.4 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:34]1[CH:38]=[C:37]([CH2:39][OH:40])[CH:36]=[N:35]1.[F:41][C:42]1[CH:49]=[C:48](O)[CH:47]=[CH:46][C:43]=1[C:44]#[N:45]>O1CCCC1>[F:41][C:42]1[CH:49]=[C:48]([O:40][CH2:39][C:37]2[CH:36]=[N:35][S:34][CH:38]=2)[CH:47]=[CH:46][C:43]=1[C:44]#[N:45]
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1cnsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cnsc2)cc1F
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
Diisopropyl azodicarboxylate (1.19 g) is added to a stirred solution of triphenylphosphine (1.55 g) in tetrahydrofuran (30 mL) at 0° C. under nitrogen and stirring is continued at 0° C. for 30 minutes. A solution of isothiazol-4-ylmethanol (0.34 g) and 2-fluoro-4-hydroxybenzonitrile (0.4 g) in tetrahydrofuran (30 mL) is added at such a rate that the temperature did not exceed 0° C. After the addition is complete stirring is continued at 0° C. for 30 minutes then at ambient temperature for 24 hours. The reaction mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed with water (50 mL), with brine (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated to give 2-fluoro-4-(isothiazol-4-ylmethoxy)benzonitrile (0.24 g), m.p. 102-105° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[O-]CCCC.[Sn+4:14].[O-]CCCC.[O-]CCCC.[O-]CCCC>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Sn+4:14].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2]
Reactant: Oc1ccccc1O
Agent: CCCC[O-]
Agent: [Sn+4]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (2.20 g, 20.0 mmol) and toluene (25 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 4.11 g (10.0 mmol) of tin(IV) butoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, volatile components of the residual mixed solution were vaporized under reduced pressure by a rotary evaporator. The residual solid content was further heated to 100° C. under vacuum using a vacuum dryer so that the remaining volatile components were completely removed. The solid content (catechol-tin complex) was green in color. The yield amount was 3.35 g (10.0 mmol), and the yield percentage was 100%. 6.70 g of catechol-tin complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: N#N.[Cl:3][C:4]1[N:9]=C(Cl)C(OC)=[CH:6][N:5]=1.[CH3:13][Mg]Cl.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CC1OCCC1>[Cl-:3].[CH3:20][O:19][C:18]1[CH:6]=[N:5][C:4]([CH3:13])=[NH+:9][C:17]=1[CH3:16]
Reactant: C1CCOC1
Reactant: C[Mg]Cl
Reactant: COc1cnc(Cl)nc1Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CC1CCCO1
Product: COc1cnc(C)[nH+]c1C
Product: [Cl-]
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A three-neck round bottom flask, fitted with a mechanical stirrer, an additional funnel, a temperature probe and N2 inlet was charged sequentially with 2-MeTHF (330 mL, 10.5 vol, water content: <300 ppm), 2,4-dichloro-5-methoxy-pyrimidine (16, 30.0 g, 0.164 mol) (FWD Chem, Shanghai, China, or Amfinecom, Inc., St. Petersburg, Va.), and NiCl2(dppp) (1.4 g, 2.6 mmol, 1.6 mol %). The resulting mixture was degassed by evacuation with a reduced pressure followed by purging with nitrogen gas (3 times at room temperature). The resulting mixture was cooled to 15° C. and a solution of 3 M Methyl magnesium chloride in THF (125 mL, 2.25 equiv.) was added via a dropping funnel maintaining the internal temperature at 15-25° C. over a period of 1.5 h (Note: first 6 mL of MeMgCl was added slowly at 15-20° C., and aged for 15 min to activate the catalyst). The dropping funnel was rinsed with 2-MeTHF (15 mL). After addition of the MeMgCl, the reaction was warmed to room temperature over 1 h with the aid of a cooling water-bath. The reaction was stirred for 13 h at room temperature with water-bath cooling (At this point, HPLC indicated the reaction was complete. Magnesium salt was precipitated as a golden yellow colored slurry). The resulting slurry was transferred into the pre-cooled (10° C.) 15% aqueous citric acid solution (300 mL) via cannula at such a rate to maintain the temperature below 30° C., and the biphasic mixture was vigorously stirred for 15 min. The reaction flask was rinsed with 2-MeTHF (60 mL). After stirring for 15 min, ammonium hydroxide (28%, 150 mL) was added keeping the temperature below 30° C. (the pH of the aq. Layer: ˜10). The biphasic mixture was stirred for an additional 15 min. At this point, sodium chloride (83 g) was added and allowed to dissolve (=20 min) After phase separation, the aqueous layer was back-extracted with 2-MeTHF (300 mL). After a phase-cut, the organic layers were combined, concentrated and azeotropically dried (below 40° C.) by 2-MeTHF flush (300 mL). The precipitated inorganic salt was filtered through an in-line CUNO-filter, and rinsed with 120 mL of 2-MeTHF. The rinse was combined with the initial filtrate.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-]>CO>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Yield: 5.9 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (75 mg, 0.23 mmol), methylurea (34 mg, 0.46 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. % , 0.49 mL, 0.35 mmol) and methanol (0.5 mL) was heated at 100° C. for 8 h. Over time, the reaction mixture turned cloudy in appearance. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 30/70 hexanes/ethyl acetate) afforded 1-[2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-3-methyl-urea (5 mg, 6%) as a colorless oil: FAB-HRMS m/e calcd for C17H24N2O5S (M+H)+ 369.1484. found 369.1495.