Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=[O:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+]>CO.C1COCC1>[CH2:12]([O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:1][OH:2])[C:7]#[N:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)c(OCc2ccccc2)c1

Procedure:
33.1 g of 4-formyl-3-hydroxybenzonitrile (Liebigs Ann. Chem. (1982) 1836) were O-benzylated with 1 eq. each of benzyl bromide and K2CO3 and, after workup, reduced with NaBH4 in 100 ml of MeOH/THF 2:3 at −10° C. to 0° C. to give the alcohol. 22.4 g were obtained. The product could be crystallized from DCM/petroleum ether.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1)c1ccc([N+](=O)[O-])cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3)cc2)c1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A high-pressure vial was filled with the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide (50 mg, 0.1 mmol, 1 equiv), the phenylboronic acid (19 mg, 0.15 mmol, 1.5 equiv), K2CO3 (29 mg, 0.2 mmol, 2 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 equiv), dioxane (1.5 mL) and water (0.3 mL). The mixture was degassed for 5 min under argon atmosphere and the vial was sealed. The reaction mixture was heated at 100° C. for 30 min under microwaves. The solution was then concentrated in vacuo, filtered and purified by preparative HPLC to afford a beige powder (50 mg, 0.1 mmol, 100%). ESI-MS (m/z): 476 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:31](=[O:32])[CH2:30][OH:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: O=C(O)CO
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)CO)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared (38 mg, 15%), using a procedure analogous to Example 154, starting from N-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol) and glycolic acid (51 mg, 0.667 mmol). NMR: 1.39 (d, 6H), 1.91-2.04 (m, 1H), 2.13-2.25 (m, 1H), 2.44 (s, 3H), 3.04-3.12 (m, 1H), 3.18-3.47 (m, 3H), 3.80 (d, 2H), 4.38-4.47 (m, 1H), 5.32 (t, 1H), 5.40-5.52 (m, 1H), 6.50 (d, 2H), 7.30 (s, 1H), 7.35 (d, 2H), 7.82 (d, 1H), 8.40 (d, 1H), 9.04 (s, 1H); m/z 454.
Reaction SMILES: [N+:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([O-:3])=[O:2].[O:14]=O>C(O)(=O)C>[N+:1]([C:4]12[CH2:5][CH:6]3[CH2:12][CH:10]([CH2:9][C:8]([OH:14])([CH2:7]3)[CH2:13]1)[CH2:11]2)([O-:3])=[O:2]
Reactant: O=O
Reactant: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Solvent: CC(=O)O
Product: O=[N+]([O-])C12CC3CC(CC(O)(C3)C1)C2
Yield: 48 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1-nitroadamantane, 1 mmol of NHPI and 0.05 mmol of V(AA)3, and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 8 hours. The analysis by gas chromatography revealed the formation of 1-nitro-3-adamantanol (yield: 48%) a 1-nitro-3,5-adamantanediol (yield:19%) and a 1-nitro-3,5,7-adamantanetriol (yield:2%), converted from 1-nitroadamantane at a conversion rate of 76%. These products were analyzed by mass spectrometric analysis.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH3:6]>>[CH3:3][C:2](=[CH:1][N:6]=[CH:1][CH:2]([CH3:4])[CH3:3])[CH3:4]
Reactant: N
Reactant: CC(C)C=O
Product: CC(C)=CN=CC(C)C

Procedure:
When isobutyraldehyde was reacted under conditions similar as described in Example I, above, for the preparation of dihydrothiazoles from ketones, no incorporation of sulfur occurred. However with a variation in the reaction, secondary aldehydes could be made to yield dihydrothiazoles in excellent yield. The reaction of isobutyraldehyde with ammonia yielded, via an intermediate, 2,6-dimethyl-4-azahepta-2,4-diene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=[N:29][NH2:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:17]1([C:16](=[N:29][N:30]2[C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@@H:10]2[CH3:12])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1N=C(c1ccccc1)c1ccccc1

Procedure:
Also in accordance with Scheme 1 and starting with the reaction of t-butyloxycarbonyl-L-threonine (1b) with benzophenone hydrazone (2) in the presence of 2-ethoxy-1(2H)-quinolinecarboxylic acid ethyl ester the hydrazide derivative N-(t-butyloxycarbonyl)-L-threonine-2-(2-diphenylmethylene)hydrazide (3b) was obtained. Ring closure of (3b) as described above with diethyl azodicarboxylate and triphenylphosphine gave the β-lactam, t-butyl (S)-[1-[(diphenylmethylene)amino]-2-(S)-methyl-4-oxo-3-azetidinyl)-carbamate (4b). Catalytic hydrogenation of (4b) gave the N-amino compound t-butyl 1-amino-2-(S)-methyl-4-oxo-3-(S)-azetidinylcarbamate (5b) which was reacted with benzyl glyoxylate (6) to give the imino derivative benzyl [[4(S)-methyl-3(S)-[(t-butoxycarbonyl)amino]-2-oxo]imino]acetate (7b). Catalytic reduction of (7b) gave the amino derivative 4(S)-methyl-[[3(S)-[[(t-butyloxycarbonyl]amino]-2-oxo-1-azetidinyl]imino]acetic acid (8b) which was treated with trifluoroacetic acid to give the amino acid, [[(S)-3-amino-4-oxo-2-(S)-methyl-1-azetidinyl]iminoacetic acid trifluoroacetate (9b). Then condensation of the trimethylsilyl derivative (10b) with the activated ester of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (11) gave the desired monobactam derivative (S)-3-[2-(2-amino-4-thiazolyl)]-(Z)-2-methoxyiminoacetylamino-2-(S)-methyl-4-oxo-1-azetidinyliminoacetic acid (12b). ##STR3##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6](=[O:9])[C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Br.O>C(Cl)Cl>[Cl:8][C:7]1[C:6](=[O:9])[N:5]([CH2:19][O:20][CH3:21])[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCn1ncc(Cl)c(Cl)c1=O
Reaction time: 22 h
Yield: 74.8 %

Procedure:
To a stirred solution of 4,5-dichloropyridazin-6-one (5.00 g, 30.3 mmol) and N,N-diisopropylethylamine (7.92 mL, 45.5 mmol) in methylenechloride (50 mL) was added slowly, bromomethyl methyl ether (4.79 mL, 60.6 mmol) at room temperature (water-bath). The reaction was stirred for 22 h and was then concentrated. Purification by column chromatography (1% MeOH in CH2Cl2) gave 4.74 g (74.8%) of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]([F:38])([F:37])[F:36])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:36])([F:37])[F:38])[N:25]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1cscc1C

Procedure:
Oxalyl chloride (123 μL; 1.45 mmol; 3 eq.), Intermediate 29 (120 mg; 0.48 mmol; 1 eq.), Intermediate 2 (106 mg; 0.48 mmol, 1 eq.) and DIEA (250 pit; 1.45 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7]CS([O-])(=O)=O)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].FC(F)(F)C1N=C(C(F)(F)F)NN=1.C(=O)([O-])[O-:30].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:1][C:2]1[S:6][C:5]([CH2:7][OH:30])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1sc(CCS(=O)(=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: FC(F)(F)c1n[nH]c(C(F)(F)F)n1
Agent: [K+]
Solvent: CC#N
Product: Cc1sc(CO)cc1[N+](=O)[O-]

Procedure:
1.0 g (3.98 mmol) (5-methyl-4-nitro-2-thienyl)methylmethane sulphonate, 0.82 g (3.98 mmol) 3,5-bis(trifluoromethyl)-1H-1,2,4-triazole, 0.93 g (5.97 mmol) potassium carbonate and 0.11 g (0.398 mmol) 18-crown-6 are heated under reflux in acetonitrile for 2 h. The cooled reaction mixture is evaporated, the residue taken up in 20 ml water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is distilled off under vacuum. The product (1-[(5-methyl-4-nitro-2-thienyl)methyl]-3,5-bis(trifluoromethyl)-1H-1,2,4-triazole) is used in the next stage without purification.
Reaction SMILES: C[C@H]1CCCCN1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](N)CC3)C=CC2=NN=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][C@@H:32](C)[N:31]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH:57][C:58](=[O:80])[NH:59][C:60]4[N:64]([C:65]5[CH:66]=[N:67][N:68]([CH2:70][CH2:71][O:72]S(C)(=O)=O)[CH:69]=5)[N:63]=[C:62]([CH:77](C)[CH3:78])[CH:61]=4)[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1>>[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH:57][C:58]([NH:59][C:60]4[N:64]([C:65]5[CH:66]=[N:67][N:68]([CH2:70][CH2:71][OH:72])[CH:69]=5)[N:63]=[C:62]([CH2:77][CH3:78])[CH:61]=4)=[O:80])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Agent: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: CCc1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCO)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 2 (150 mg, 0.397 mmol), and Intermediate Cb (157 mg, 0.397 mmol) by using an analogous procedure to that described for Intermediate A step d. LCMS (Method 3): Rt 3.10 min, m/z=625 [MH+].
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:37]([C:40](O)=[O:41])[CH2:38][OH:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:22][C:38](=[O:39])[C@H:37]([CH2:40][OH:41])[NH:36][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.3 %

Procedure:
To a solution of L-glutamic acid 1,5-dibenzyl ester p-toluenesulfonate (10.0 g), Boc-Ser (4.1 g) and TEA (2.0 g) in DMF (200 ml) are added with stirring WSC (5.0 g) and HOBt (4.0 g) under ice-cooling. The mixture is stirred at room temperature for 20 hours, and thereto is added ethyl acetate (200 ml). The mixture is washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The precipitated solid is collected by filtration, and washed with ether to give N-tert-butoxycarbonyl-L-seryl-L-glutamic acid 1,5-dibenzyl ester (9.7 g) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCCC1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]3[CH:21]=[CH:22][C:23]([Br:25])=[CH:24][C:19]=3[S:18](=O)(=O)[C:17]=2[CH:28]=1.[OH-].[Na+]>C(O)C.O>[Br:25][C:23]1[CH:22]=[CH:21][C:20]2[C:16]3[CH:15]=[CH:14][C:13]([Br:12])=[CH:28][C:17]=3[S:18][C:19]=2[CH:24]=1
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Brc1ccc2c(c1)sc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Into a 1 L 3-necked round-bottomed flask equipted with a reflux condenser, nitrogen inlet, magnetic stirring bar and a heating mantle was place 4.63 g (0.122 mol) of LiAlH4, and 600 mL of dry tetrahydrofuran (THF) (distilled from benzophenone ketyl). To this was added 18.31 g (0.0489 mol) of 3,7-dibromodibenzothiophene-5,5-dioxide. The mixture was stirred overnight at room temperature, then refluxed for 1 hour. To the cooled mixture was added 5 mL H2O, 5 mL of 15% NaOH, followed by 15 mL of water. After stirring for 2 hours at room temperature the coagulated salts were filtered and washed with THF. The combined THF extracts were condensed to give 20 g of crude material. This was taken up into 1.5 L of hot ethanol, filtered and cooled. The yellow precipitate was suction filtered and air dried to give 5.2 g of 3,7-dibromodibenzothiophene: mp 174.5-176. Molecular ions by mass spectroscopy had molecular weights of 340, 342 and 344 (due to different isotopes of Br).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:26])=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=3[C@@:15]32[CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1)=[N+]=[N-].C(O)C>[Pd].CCOC(C)=O>[F:26][C:10]1[C:9]2[O:8][C:7]3[C:16](=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=3)[C@@:15]3([CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)[C:14]=2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(N)ccc1O2
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
To a disposable vial was charged with (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (170 mg, 0.458 mmol), Ethanol (1.7 ml) and EtOAc (0.8 ml). The heterogeneous mixture stirred for 5 min and palladium on carbon (48.7 mg, 0.046 mmol) was added to the vial. The mixture was hydrogenated (balloon) at room temperature overnight. The mixture was filtered through celite and concentrated. The dark residue was diluted with DCM and concentrated again. After drying in vacuo, (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthene]-2,7′-diamine (120 mg, 0.347 mmol, 76% yield) was obtained as tan foam. It was used for next step without further purification.
Reaction SMILES: [CH:1]#[C:2][C:3]#[CH:4].[OH-].[K+].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([C:1]#[C:2][C:3]#[CH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CC#C
Reactant: c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: C#CC#Cc1ccccc1

Procedure:
The thus-obtained diacetylene derivative represented by the formula (IX) is then dissolved in benzene and refluxed while being heated for 30 min. to 1 hour in the presence of potassium hydroxide. After the reaction has been completed, the reaction mixture is filtered, and the solvent is then evaporated. The residure is then purified by silica-gel column chromatography to obtain a phenylbutadiyne derivative represented by the formula (X).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])=[CH:6][C:5]=1[CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [4-methoxy-2′-(2-oxo-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.060 g, 1.42 mmol) in 1,4-dioxane:H2O (2:1; 2 mL) was added lithium hydroxide (14 mmol), and the reaction was stirred overnight at room temperature. The pH was adjusted to pH6 with 10% aqueous HCl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. M+H is 410.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])/[CH:55]=[C:50]2\[S:51][C:52]([CH3:54])=[N:53][N:49]\2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 4-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.85-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.67-1.80 (m, 2 H) 2.49 (s, 3 H) 4.20-4.23 (m, 2 H) 6.70 (m, 1 H) 7.64 (d, 2 H) 7.94 (d, 2 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([N:8]([CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:19][CH:20]=2)(=[O:11])=[O:10])[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
300 mg of 4-[((3-chloro-2-methylphenyl){2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid was dissolved in 5.00 mL of THF, and 340 mg of ethyl chloroformate and 326 mg of triethylamine were added thereto, followed by stirring at room temperature for 1 hour. To the reaction liquid was added dropwise an aqueous solution (0.80 mL) of 360 mg of sodium borohydride over 30 minutes, followed by stirring at room temperature for 2 hours. The reaction liquid was acidified with addition of 8.0 mL of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) to obtain a product, which was crystallized from diisopropyl ether to obtain 118 mg of N2-(3-chloro-2-methylphenyl)-N2-{[4-(hydroxymethyl)phenyl]sulfonyl}-N-(4-methoxybenzyl)glycinamide.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and phenylboronic acid. The title compound was obtained in 48% yield as white foam. MS (m/e): 482.3 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1)[CH:23]=[CH2:22]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(Br)ccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(C)cc(Oc3ccc(C#N)cc3)nc2c1

Procedure:
6.8 g (0.02 mol) of 4-[(7-bromo-4-methyl-quinolin-2-yl)-oxy]-benzonitrile, 6.8 g (5.9 mmol) of tetrakis-(triphenylphosphine)-palladium (0) and 6.8 ml (0.022 mol) of allyltributyltin are refluxed in 50 ml toluene under a nitrogen atmosphere for 2 hours. The toluene is distilled off, the residue triturated with ether and suction filtered. The mother liquor is combined with silica gel and evaporated down. Then the mixture is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate (95:5 and 9:1). The desired fractions are combined and evaporated down.