Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[Cl:9])([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To solution of 1,3-dichloro 4-iodobenzene (1.0 g, 3.66 mmol) in tetrahydrofuran (10 mL) at −20° C. was added isopropyl magnesium chloride (2M in tetrahydrofuran, 1.9 mL, 3.84 mmol). The solution was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.73 g, 3.66 mmol) in tetrahydrofuran (5 mL) was added. The solution was allowed to warm to room temperature with stirring for 18 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (3×10 mL). The organic extracts were combined, washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol (20 mL) followed by addition of sodium borohydride (0.14 g, 3.66 mmol). The resulting mixture was left stirring for 30 min. Methanol was removed in vacuo. Water (20 mL) was added to the residue and extracted with ethyl acetate (25 mL). The organic phase was dried over sodium sulfate. The gum obtained was chromatographed on silica gel using dichloromethane/methanol from 100% to 98% dichloromethane in a gradient fashion, to give the title compound as a white foamy solid (0.38 g, 30%). The material was used in next reaction without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]=1>ClCCl>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (100 mmol) and N,N-diisopropylethyl amine (130 mmol) in dichloromethane (500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) was added dropwise under nitrogen. The solution was stirred for one hour as it returned to room temperature. The reaction mixture was filtered through a sica gel pad, washed with 0.5 N sodium hydroxide and water, dried over anhydrous magnesium sulfate. The solution was again filtered through a silica gel pad and evaporated to dryness in vacuo. The residual oil crystallized from diethyl ether to provide the title compound as a colorless crystalline solid, m.p. 165–167° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](I)[CH:5]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccnc(I)c1
Product: COC(=O)c1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=281.0 (M+) was obtained as a light brown solid (59% yield) by the reaction of 2-iodo-isonicotinic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 46 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.15 g of 2-chlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(2-chlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (19)), m.p.: 76.2° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:18]2[C:5](=[C:6]3[C:15](=[CH:16][CH:17]=2)[C:14]2[CH:13]=[CH:12][C:11]([OH:19])=[CH:10][C:9]=2[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.[H-].[Na+].Br[C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33]>O>[CH3:35][C:31]([O:19][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:6]([CH2:7][CH2:8][C:9]=2[CH:10]=1)=[C:5]1[C:18]([C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1)=[CH:17][CH:16]=3)([CH3:36])[C:32]([OH:34])=[O:33]
Reactant: CC1(C)CCc2c1ccc1c2CCc2cc(O)ccc2-1
Reactant: CC(C)(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(Oc1ccc2c(c1)CCc1c-2ccc2c1CCC2(C)C)C(=O)O

Procedure:
To a solution of 19 parts of 7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[ a]phenanthren-3-ol in 800 parts of toluene is added 13 parts of a 50% dispersion of sodium hydride in mineral oil. The resultant mixture is stirred and heated at the boiling point under reflux in an atmosphere of nitrogen for 1 hour, then cooled, whereupon approximately 13 parts 2-bromo-2-methylpropanoic acid is introduced. The mixture thus obtained is stirred and heated at the boiling point under reflux in a nitrogen atmosphere for 4 hours, at which point heating is discontinued. The mixture is stirred 18 hours longer at ambient temperatures, then approximately 250 parts of water is cautiously introduced. The mixture so produced is extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. Crystallization of the residue from a mixture of ether and hexane affords 2-methyl-2-[(7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phenanthren-3-yl)oxy]propanoic acid melting at 167°-170°, and having the formula ##STR7##
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1cccc(Cc2cc(-c3ccc(N)nc3N)on2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (43 mg, 21%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].ClC1C([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=CC=CC=1N>>[Cl:9][C:7]1[CH:6]=[C:4]([CH:3]=[C:2]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:8]=1)[NH2:5]
Reactant: Nc1cc(Cl)cc(Br)c1
Reactant: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: CC1(C)OB(c2cc(N)cc(Cl)c2)OC1(C)C
Yield: 48 %

Procedure:
This material was prepared from 3-bromo-5-chloroaniline following a similar procedure used for SM-9, step 3. The crude product was purified by flash chromatography (RediSep Cyano®, Teledyne ISCO, 0-50% EtOAc in hexanes) to afford 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48%) as a pale orange solid: LCMS(m/z) 172.1 (MH+), tR=0.33 minute.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([N:35]4[CH2:42][CH2:41][CH2:40][CH:36]4[C:37]([OH:39])=[O:38])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Product: O=C(O)C1CCCN1C(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Yield: 15 %

Procedure:
Compound 233 was synthesized from Compound 201 as described for Compound 235, except L-proline was used instead of L-5-hydroxytryptophane. Yield: 15%.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In the same manner as that described under (b), 516 mg of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (crude product) in 5.1 ml of glacial acetic acid are reduced with 94 mg of sodium borohydride and worked up. The title compound having the properties mentioned under (a) is obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[Br:19][C:20]1[CH:21]=[C:22]([CH3:27])[C:23](F)=[N:24][CH:25]=1.O>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:23]1[C:22]([CH3:27])=[CH:21][C:20]([Br:19])=[CH:25][N:24]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: Cc1cc(Br)cnc1F
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
Sodium hydride (60%, 0.18 g, 4,5 mmol) was added to a solution of 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (1.0 g, 4.5 mmol) in dry THF (25 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. The pyridine product of Example 1 (0.86 g, 4.5 mmol) was added to this reaction mixture and stirred for 16 hours. Water (20 mL) was added and the resulting mixture was extracted with ether (3×50 mL), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield crude residue (1.5 g), which was then triturated with ether/pentane to give α-(methoxyimino)-N-methyl-2-[[[5-bromo-3-methyl-2-pyridinyl]oxy]methyl]-benzeneacetamide (1.1 g) as a white solid. M.P. 115-116° C.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:32][C:33](=[O:39])[CH2:34][C:35]([CH2:37][Cl:38])=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH2:24]([O:32][C:33](=[O:39])[CH2:34][C@@H:35]([OH:36])[CH2:37][Cl:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCOC(=O)CC(=O)CCl
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCCCCCCCOC(=O)C[C@@H](O)CCl
Reaction time: 24 h
Yield: 69.4 %

Procedure:
Resting Cells. One hundred grams of commercial fresh baker's yeast Saccharomyces cerevisiae (Red Star) was suspended in 250 ml of tap water to which was added 10 g of sucrose and 3.6 g of γ-chloroacetoacetic octyl ester. After the contents were incubated at 25° C. on a rotary shaker (250 cycles/minute- 2" radius) for 24 hours, an additional 10 q of sucrose was added to the flask and the reaction was allowed to proceed for another 24 hours. The cells were then removed by filtration through a pad of celite. The cells were washed with water and ethyl acetate. The washings were combined with the filtrate and exhaustively extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4 and evaporated to give an oily residue, which was chromatographed over a silica gel column to yield 2.52 g of 4-chloro-3(R)-hydroxybutyric acid octyl ester, as a low melting solid; [α]23 +13.2° (c, 4.0,CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH2:28][CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[OH:31].C(N(C(C)C)C(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[OH:31])=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(O)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), 2-amino-1-(4-chlorophenyl)ethanol hydrochloride (0.033 g, 0.16 mmol), N-ethyl-N-isopropylpropan-2-amine (0.030 ml, 0.17 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018 g, 0.13 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred at ambient temperature for 16 hours. It was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system using a 25-100% EtOAc/hexanes linear gradient to yield 56 mg of the title compound (80% yield).
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH3:29]>CN(C)C=O>[CH3:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][NH:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)[CH3:16]
Reactant: CCOc1ccccc1OCCBr
Reactant: COc1ccc(CC(C)N)cc1S(N)(=O)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
5-(-2-aminopropyl]-2-methoxybenzenesulfonamide (200 g) was dissolved in dimethylformamide (950 ml) and 1-(2-Bromoethoxy)-2-ethoxybenzene (100.3 g) was added. The reaction mixture was heated to 80-85° C. for 4 hours. Dimethylformamide was then distilled off under vacuum. Water (1000 ml) was added to solid residue and the mixture was heated to 80-90° C. under stirring for 2 hours. The mixture was cooled to room temperature. Formed crystals were filtered off and were suspended in water (900 ml). Suspension was heated to 80-90° C. under stirring for 2 hours. Crystals were filtered, washed with water (200 ml) and dried to give tamsulosin base (150 g, 89.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)#[CH:20].CCN(C(C)C)C(C)C.CCOC(C)=O>C1COCC1.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(I)cc1
Reactant: C#Cc1ccc(OCCC)cc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOc1ccc(C#Cc2ccc(C(C)CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.00 g (2.77 mmol) [2-(4-iodo-phenyl)-propyl]-carbamic acid tert-butyl ester (152.8) and 0.44 g (2.77 mmol) 1-ethinyl-4-propoxybenzene in 25 mL THF are added 0.78 mL (5.54 mmol) DIPEA, 40.5 mg (0.06 mmol) [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and 10.6 mg (0.055 mmol) CuI. The reaction mixture is stirred at r.t. for 3 h. EtOAc is added and the mixture is washed with diluted aq. ammonia solution (1×) and water (1×), dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 9/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.[I-].[K+]>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:10]
Reactant: Cc1cc(C)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(Cl)cc(CBr)c1
Yield: 109.1 %

Procedure:
A solution of 5-chloro-m-xylene (59.3 g) and dibenzoyl peroxide (5.0 g) in 1.13 L of benzene was heated at reflux. N-Bromosuccinimide (82.2 g) was added in portions over 15 minutes. Heating was continued for an additional 20 minutes until a negative potassium iodide reaction was observed. The reaction mixture was cooled, evaporated and then titurated with hexane (500 ml). The precipitated succinimide was removed by filtration and washed with additional hexane. Concentration afforded 101 g of crude 3-chloro-5-methylbenzyl bromide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(O)c1
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-hydroxybenzoic acid (24.7 grams, 0.2 mole) and acetic anhydride (40.8 grams, 0.4 mole) were mixed and heated to reflux for 3 hours. The reaction mixture was poured into water and stirred for 3 hours at room temperature. The product precipitated, was collected by filtration and recrystallized from chloroform. Yield was 21grams (58%) of white crystals. Melting point was 128°-129.5° C. Proton NMR conducted as in the preceeding preparation, but using (DMSO-d6) gave as peaks, in ppm: 2.24 (s,3H), 7.35, 7.55, 7.65, 7.8 (m, 4H), 13.2 (b, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])=[O:12])(C(C)(C)C)(C)C.[Cl-].[NH4+]>C(O)(=O)C.C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OCCC(=O)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CCO)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
(R)-4-[3-(tert-Butyldimethylsilyloxy)-1-oxopropyl]-3-[[(S)-1-(phenylmethyloxycarbonyl)-2-pyrrolidinyl]carbonyl]thiazolidine (215 mg) was dissolved in a mixture of acetic acid-THF-water (3:1:1, 3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated ammonium chloride and extracted with chloroform. The organic layer was washed with water, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (silica gel, developing solvent: chloroform-methanol) to give the title compound (97 mg) (see Table 5).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine (Step 15.1). Title compound: ES-MS: 522.0 [M+H]+; single peak at tR=3.15 min (System 1); Rf=0.19 (CH2Cl2/MeOH+1% NH3aq, 9:1).