Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[C:10]1=NC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[I:20].[C:21](#[N:23])C>>[I-:20].[CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[C:10]1=[CH:21][NH3+:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC#N
Reactant: CCCN1CCN(N=Cc2ccccc2)C1=NC
Product: CCCN1CCN(N=Cc2ccccc2)C1=C[NH3+]
Product: [I-]

Procedure:
A mixture of 0.51 g of 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine in 15 ml of acetonitrile with 0.36 g of methyliodide is refluxed for ca. one hour and the solvent is evaporated off. The residue is treated with acetonitrile and the solvent is evaporated off. (1-benzylideneamino-3-propyl-imdazolidine-2-yliden)methyl-ammonium iodide is obtained in the form of a powder.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][C:7]([Br:31])=[C:8]([C:10](=[N:28][O:29][CH3:30])[C:11]([NH:13][CH:14]2[C:26](=[O:27])[N:16]3[C:17]([C:23]([OH:25])=[O:24])=[CH:18][CH:19]([O:21][CH3:22])[S:20][C@H:15]23)=[O:12])[N:9]=1)=O.C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[S:6][C:7]([Br:31])=[C:8]([C:10](=[N:28][O:29][CH3:30])[C:11]([NH:13][CH:14]2[C:26](=[O:27])[N:16]3[C:17]([C:23]([OH:25])=[O:24])=[CH:18][CH:19]([O:21][CH3:22])[S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(OC)S[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(OC)S[C@H]12)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Conc. hydrochloric acid (0.7 ml.) was added to a solution of 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.) in methanol (45 ml.) and stirred at room temperature for 2 hrs. and further for 3.5 hrs. under ice-cooling. The reaction mixture was treated with activated charcoal. Water (30 ml.) was added to the solution and adjusted to pH 6.5 with 1N-aqueous sodium hydroxide, and methanol was distilled off. Ethyl acetate was added to the residue and adjusted to pH 2.5 with 1N-hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate solution obtained above and the washings were combined, dried over magnesium sulfate, treated with activated charcoal and evaporated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem- 4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: C(NC1SC=C(C(=NOC)C(N[CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([CH3:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O>[CH3:44][N:43]1[C:39]([S:38][CH2:37][C:34]2[CH2:35][S:36][C@@H:31]3[CH2:30][C:48](=[O:49])[N:32]3[C:33]=2[C:45]([OH:47])=[O:46])=[N:40][N:41]=[N:42]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A mixture of 1.4 g of the product of Example 3 and 5 ml of 50% aqueous formic acid was held on a water bath at 55° C. for 15 minutes and then 5 ml of water were added. The mixture was cooled and vacuum filtered and the filtrate was concentrated after the addition of 5 ml of ethanol. The residue was taken up in 5 ml of ethanol and the mixture was triturated and was vacuum filtered. The product was washed with ethanol and then ether, was vacuum filtered, dried and washed to obtain 0.557 g of pure 7-[{2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-ceph-3-eme-4-carboxylic acid in the syn configuration.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N+:13]([O-])=[O:14])=[CH:7][N:6]=1.CO.C[O-].[Li+].C(Cl)[Cl:26]>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:12]([Cl:26])=[N:13][OH:14])=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccccc2F)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 2-(2-fluoro-phenoxy)-5-(2-nitro-ethyl)-pyridine (150 mg, 0.59 mmol) described in Manufacturing Example 74-1-3 and methanol (1.5 mL) was added lithium methoxide (45 mg, 1.2 mmol) at room temperature, which was stirred for 5 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. Titanium (IV) chloride (140 μL, 1.3 mmol) was added at −78° C. to a mixture of the resulting residue, methylene chloride (2 mL) and tetrahydrofuran (1 mL), and stirred for 80 minutes at 0° C. The reaction mixture was cooled to −78° C., water (1 mL) was added, and the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water until the pH was 5, and then washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and was concentrated under a reduced pressure to obtain the title compound (160 mg) as a crude product. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)C(Br)CC(O)=O)=[CH:3][CH:2]=1.ClCCl.CO.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]#[C:27][C:26]([OH:29])=[O:28])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(Br)C(Br)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared analogously to Example 3.4.b. from 3-biphenyl-4-yl-2,3-dibromopropanecarboxylic acid. Yield: 2.8 g (96.8% of theory); C15H10O2 (M=222.24); melting point: 170° C.; calc.: molecular ion peak (M+H)+: 223; found: molecular ion peak (M+H)+: 223; Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid (90:10:1)).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7](=[O:20])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7](=[O:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC(=O)N(CC#CCN2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C[C@H](O)CN1CC#CCN1CCCCC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 1.0 g of (S)-4-(acetyloxy)-1-[4-(1-piperidinyl)-2-butynyl]-2-pyrrolidinone, 0.75 g of sodium carbonate and 40 ml of methanol was stirred overnight, then filtered and concentrated. The residue was concentrated from dichloromethane and purified by chromatography on deactivated alumina, giving 0.83 g of the desired product as a yellow oil [α]D260 =-8° (c, 1.018, dichloromethane).
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][CH2:8][C@H:9]([NH:23][C:24]([C:26]1[N:30]2[C@:31]([CH3:56])([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=3)[C:32](=[O:43])[N:33]([C:34]3[CH:39]=[C:38]([Cl:40])[C:37]([F:41])=[C:36]([Cl:42])[CH:35]=3)[C:29]2=[N:28][CH:27]=1)=[O:25])[C:10](=[O:22])[NH:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][CH3:14])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:40][C:38]1[CH:39]=[C:34]([N:33]2[C:29]3=[N:28][CH:27]=[C:26]([C:24]([NH:23][C@H:9]([C:10](=[O:22])[NH:11][C:12]([CH3:21])([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:13][CH3:14])[CH2:8][CH2:7][C:6]([OH:57])=[O:5])=[O:25])[N:30]3[C@:31]([CH3:56])([CH2:44][C:45]3[CH:46]=[CH:47][C:48]([O:51][C:52]([F:54])([F:53])[F:55])=[CH:49][CH:50]=3)[C:32]2=[O:43])[CH:35]=[C:36]([Cl:42])[C:37]=1[F:41]
Reactant: CCC(C)(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)c(F)c(Cl)c1)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(C)(NC(=O)[C@H](CCC(=O)O)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)c(F)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.7 %

Procedure:
To a solution of (S)-4-{[(R)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-methyl-1-pyridin-2-yl-propylcarbamoyl)-butyric acid tert-butyl ester (116 mg, 0.142 mmol) in 2 mL of CH2Cl2 was added HCl in dioxane (0.177 mL, 0.708 mmol). The reaction mixture was stirred at room temperature for 6 h. An additional portion of HCl in dioxane (0.177 mL, 0.708 mmol) was added, and the reaction mixture was stirred for 4 h and then concentrated to a colorless oil. The residue was purified by reverse-phase HPLC (20-90% CH3CN/H2O, 0.1% TFA) to give 45 mg (42%) of the title compound, isolated as the TFA salt, m/z 763.8 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.C[N:16](C)[CH2:17][CH2:18][CH2:19][N:20]=[C:21]=NCC.C[N:27](C)[CH:28]=[O:29]>CN(C)C1C=CN=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:4][C:5]2[CH:6]=[C:7]3[C:28](=[O:29])[NH:27][N:16]=[CH:17][C:18]4=[CH:19][NH:20][C:21]([CH:13]=2)=[C:8]34)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(=O)Nc1ccc(C(=O)Nc2cc3c4c(c[nH]c4c2)C=NNC3=O)cc1

Procedure:
Preparation of example 197 from the title compound of Example 2 (124 mg, 0.525 mmol), 4-acetylamino-benzoic acid (113 mg, 0.631 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (120 mg, 0.628 mmol), and 4-dimethylaminopyridine (77 mg, 0.631 mmol) in N,N-dimethylformamide (7.0 mL) was carried out analogously to Example 190, Step 2. When the reaction was judged complete, the volatile components were evaporated and methanol was added. The mixture was filtered to collect the solids, which were then washed with methanol, dichloromethane and diethyl ether. After drying, the title compound (32 mg, 0.0886 mmol) was obtained as a yellow powder in 17% yield.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][N:12]2[C:16]([CH2:17][OH:18])=[C:15]([Cl:19])[N:14]=[C:13]2[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)#[N:2].[CH3:30]C(C)([O-])C.[K+].CI.O>CS(C)=O>[C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16]([CH2:17][O:18][CH3:30])=[C:15]([Cl:19])[N:14]=[C:13]2[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:24][CH:25]=1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2C#N)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 0.29 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 8.0 mL of dimethyl sulfoxide at 25° was added 0.93 g of potassium t-butoxide followed by 0.060 mL of methyl iodide. The reaction mixture was stirred at 25° for 2.5 hours and then was poured into water. The aqueous emulsion was extracted with ethyl acetate; the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 5-25% ethyl acetate/benzene) furnished 0.17 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3): δ 7.72-7.57 (m, 3H); 7.43 (m, 1H); 6.94 (s, 4H); 5.22 (s, 2H); 5.04 (s, 2H); 4.27 (s, 2H); 3.26 (s, 3H); 2.56 (t, 2H); 1.65 (quint., 2H); 1.33 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=1.O>CN(C=O)C>[CH3:19][C:17]1[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=[C:14]([O:13][CH2:12][CH2:11][N:3]2[CH2:8][CH2:7][O:6][CH2:5][C:4]2=[O:9])[CH:18]=1
Reactant: O=C1COCCN1
Reactant: Cc1cc(OCCCl)nn1-c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCN2CCOCC2=O)nn1-c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1.63 mmol) in DMF (3 ml), cooled to 0-5° C., a solution of morpholin-3-one (91 mg, 0.91 mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0.7 mmol) in DMF (4 ml) was added and the mixture was heated to 50° C. for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one (192 mg, 78%) was obtained as an amorphous white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[O:4][CH:3]=1.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17]>CO>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH:3]=[C:2]([NH:1][C:15](=[CH:14][C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:12])[C:10]=2[CH:9]=1
Reactant: Nc1coc2ccc(Cl)cc2c1=O
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C=C(Nc1coc2ccc(Cl)cc2c1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 3-amino-6-chlorochromone (8 g, 0.041 mole) and dimethyl acetylenedicarboxylate (10.5 g, 0.074 mole) in methanol (150 ml) was stirred at room temperature for 2 days. The product was filtered off and washed with methanol. Recrystallization from ethyl acetate gave yellow crystals (11 g, 80%), m.p. 158°-160°.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([CH2:13][CH2:14][CH2:15][CH2:16][B:28]1[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(CCc1ccccn1)(NC(C)=O)C(=O)NC(C)(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCc1ccccn1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(2-(pyridin-2-yl)ethyl)hex-5-enamide (810 mg, 2.45 mmol) in dichloromethane (4 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (35 mg, 2 mol %) and 1,2-bis(diphenylphosphino)ethane (42 mg, 4 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.76 mL, 5.20 mmol) was added dropwise, and the reaction was then stirred overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-10% methanol in dichloromethane) gave 2-acetamido-N-tert-butyl-2-(2-(pyridin-2-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (787 mg, 70%). ESI MS found for C25H42BN3O4 m/z [460.3 (M+1)].
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.CN(C=O)C.[C:14](Cl)(=[O:18])[C:15](Cl)=O.[CH2:20](N(CC)CC)[CH3:21]>C(Cl)Cl>[CH2:20]([O:8][C:6]1[C:1]2([CH2:2][CH:3]=[CH:4][CH2:5]2)[C:14](=[O:18])[CH:15]=1)[CH3:21]
Reactant: O=C(O)C1CC=CC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC1=CC(=O)C12CC=CC2
Reaction time: 168 h
Yield: 72.7 %

Procedure:
A solution of cyclopent-3-ene carboxylic acid (4.0 g, 36.0 mmol) and DMF (0.25 ml) in DCM (30 ml) at 0° was treated dropwise with oxalyl chloride (3.5 ml, 39.0 mmol). After 2 h the reaction mixture was concentrated in vacuo, the residual slurry diluted with Et2O (100 ml) and the resulting precipitate removed by filtration and the filtrate concentrated in vacuo. The resulting oil was diluted with Et2O (50 ml), treated with ethoxyacetylene (40% w/w solution in hexanes, 10 ml) followed dropwise with triethylamine (6 ml, 44.0 mmol) and the reaction stirred for 7 d. Filtration and concentration of the filtrate in vacuo followed by chromatography (SiO2, 5:1 EtOAc:hexanes) gave the title compound as a pale yellow oil (4.3 g, 73%); m/z (ES+, 70V) 164.9 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:21])[CH:9]=[CH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.[C:22](=O)(O)[O-:23].[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8](=[O:21])[CH:9]=[CH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH:22]=[O:23])=[CH:15][NH:16]2
Reactant: O=C([O-])O
Reactant: COC(=O)C=CCc1cccc2[nH]ccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)C=CCc1cccc2[nH]cc(C=O)c12
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychoride (0.65 g, 4.16 mmol) was added dropwise to DMF (3 mL) at 0° C. After 0.5 hour, Example 7b (0.81 g, 3.70 mmol) in DMF (3 mL) was added at 0° C., then the mixture warmed to 35° C. for 0.75 hour. The solution was cooled to ambient temperature and crushed ice (10 g) was added. Solid sodium bicarbonate was added and to pH 8, the mixture diluted with water (100 mL), and the aqueous extracted with ethyl acetate (3×). The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was chromatographed (eluting ethyl acetate/hexanes) to yield 0.39 g of the title compound as a purple solid; MS(CI/NH3) m/e 244 (M+H)+. 1H NMR(CDCl3, 300 MHz) δ3.68 (s, 3H), 4.26 (m, 2H), 5.14 (m, 1H), 7.06 (d, 1H), 7.18 (m, 3H), 7.84 (d, 1H), 9.09 (br s, 1H), 9.88 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>>[Cl-:2].[Cl-:7].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:20][CH:21]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(c1ccccc1)c1ccc(Cl)cc1
Product: [Cl-]

Procedure:
The reaction was proceeded by the method described in Example 1. 21.6G of PCl5 was reacted with 20.8 g of 4-chlorobenzophenone to give 24.6 g(purity 98%, yield 89%) of 4-chlorobenzophenone dichloride as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33]O)[S:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]>>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([O:6][CH2:33][C:30]1[S:31][CH:32]=[C:28]([C:26](=[O:27])[NH:25][C@@H:23]([CH3:24])[CH2:22][N:19]2[CH:20]=[CH:21][C:17]([C:11]3[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[C:9]([Cl:8])[CH:10]=3)=[N:18]2)[N:29]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CO)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(COC(=O)CN(C)C)n1
Yield: 39.5 %

Procedure:
(S)-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)methyl 2-(dimethylamino)acetate was prepared using the method of Example 34(d) starting from N,N-dimethylglycine (0.062 g, 0.597 mmol) and (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide (0.2 g, 0.498 mmol). The product was triturated using diethyl ether and purified by Flash-chromatography, respectively. Yield 39.5%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.39 (s, 6H), 3.30 (s, 2H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.60 (m, 1H), 5.43 (d, 2H), 6.63 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 7.97 (d, 1H), 8.12 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#N)=[CH:4][N:3]=1.Cl.[OH-:28].[Na+].[OH2:30]>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([OH:30])=[O:28])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc3c(N)ncc(C(=O)O)c3c2)c2c1C(=O)CC(C)(C)C2
Yield: 44 %

Procedure:
A solution of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.15 g, 0.44 mmol) in THF (2 mL) and H2O (2 mL) is treated with concentrated HCl (10 mL). The reaction mixture is microwaved at 150° C. for 1.5 h. The reaction mixture is then treated with 5 M NaOH until pH=8. The crystals formed are collected by vacuum filtration, and dried to afford 0.07 g (44%) of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxylic acid. LC/MS m/z=364 [M+H]+, RT=2.12 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=O)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:38][NH:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)N(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylic acid (154 mg, 0.299 mmol) synthesized in Example (28a) was dissolved in dichloromethane (10 mL), and dimethylamine hydrochloride (75.0 mg, 0.920 mmol), WSCI.HCl (115 mg, 0.600 mmol) and 4-dimethylaminopyridine (110 mg, 0.900 mmol) were added, followed by stirring at room temperature for 2 days under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (107 mg, yield 66%) as a white solid.