Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29](OC)[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.BrC1N=C(C(C2C=C(CC)C=C([Cl:99])C=2F)O)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([Cl:99])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CCc1cc(Cl)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCc1cc(Cl)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 221.2 (309 mg, 0.537 mmol) was converted to the chloro intermediate, then displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (rt for 15 h, 40° C. for 9 h, 50° C. for 6 h) to afford after flash chromatography (O to 50% EtOAc/hexanes gradient) 400 mg of Iintermediate 221.3 as a pale yellow solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.43 min, 918.76 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: NN
Reactant: Cc1nccnc1Cl
Solvent: O
Solvent: CCO
Product: Cc1nccnc1NN
Temperature: 90 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Hydrazine hydrate (9.66 mL, 311.14 mmol) was added to 2-chloro-3-methylpyrazine (CAS no. 95-58-9) (8 g, 62.23 mmol) in ethanol (25 mL). The resulting solution was stirred at 90° C. for 16 hours. The resulting solution was evaporated to dryness and the crude product was purified by crystallisation from toluene (125 mL) to afford 2-hydrazinyl-3-methylpyrazine (6.2 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 2.24 (3H, s), 7.61 (1H, d), 7.61 (1H, d), 7.87 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][Cl:29].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][CH2:28][Cl:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCl)c2ccccc12
Yield: 58.3 %

Procedure:
N-tert-butyloxycarbonyl-4-amino-1-naphthol (2.0 g, 7.72 mmol), potassium carbonate (5.34 g, 38.6 mmol) and 1-bromo-2-chloroethane (1.28 ml, 15.4 mmol) are heated to 80° C. in anhydrous acetonitrile (40 ml) under a nitrogen atmosphere for 1 day. The mixture is poured into ethyl acetate (250 ml) and washed with water (500 ml). The aqueous layer is re-extracted with ethyl acetate (2×100 ml), the organic layers combined and dried over anhydrous sodium sulfate. The organic layers are evaporated to dryness and the residue purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give [4-(2-chloro-ethoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.448 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:8]([C:12]#[N:13])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[Br:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:14][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[C:12]#[N:13]
Reactant: N#Cc1cccc2c1CCC(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccc2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-oxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-1; 1.5 g, 0.0087 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.8 g, 0.01046 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. It was concentrated and diluted with ice cold water (100 mL) with constant stirring; the solid residue obtained was filtered and dried to obtain the title compound. MS (M+1): 251.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1cc(CCl)ccn1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)ccn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 4-chloromethyl-2-methyl-pyridine (described in WO 2006023707) gave the title compound. ES-MS m/e (%): 504.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].ClCCl.CC(N(C)C)=O.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[S:30][CH:31]=[C:32]([C:34](Cl)=[O:35])[N:33]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[NH2:10][C:8]([C:3]1[N:4]([CH3:7])[N:5]=[CH:6][C:2]=1[NH:1][C:34]([C:32]1[N:33]=[C:29]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)[S:30][CH:31]=1)=[O:35])=[O:9]
Reactant: Cn1ncc(N)c1C(N)=O
Reactant: O=C(Cl)c1csc(-c2ccc3c(c2)CCO3)n1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)c2csc(-c3ccc4c(c3)CCO4)n2)c1C(N)=O
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
4-Amino-2-methyl-2H-pyrazole-3-carboxamide (35 mg) is introduced into dichloromethane (1 ml) and dimethylacetamide (0.5 ml), and triethylamine (50 microlitres) and 4-dimethylaminopyridine (DMAP) (spatula tip) and 2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carbonyl chloride CAS 306936-10-7 (66 mg) are added, and the mixture is left to stir at room temperature for 18.5 h. The solvent is then removed in vacuo, and preparative HPLC results in Example 2.1 as a white solid (35 mg).
Reaction SMILES: O.[OH-].[Li+].O.[CH:5]1([O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[CH:18]=[C:17]3[CH2:24][C:25]2[CH:51]=[CH:50][C:28]([C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[C:42][CH2:43][CH2:44][CH2:45][O:46]C(=O)C)(=[O:34])=[O:33])=[O:30])=[CH:27][C:26]=2[O:52][CH3:53])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1>CO.O1CCCC1>[CH:5]1([O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[CH:18]=[C:17]3[CH2:24][C:25]2[CH:51]=[CH:50][C:28]([C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[C:42][CH2:43][CH2:44][CH2:45][OH:46])(=[O:33])=[O:34])=[O:30])=[CH:27][C:26]=2[O:52][CH3:53])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CCCCOC(C)=O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CCCCO)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
0.37 g of lithium hydroxide monohydrate and 10 ml of water are added to a solution of 1.2 g of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxybenzoyl]-2-(5-acetoxy-pent-1-yn-1-yl)-benzenesulfonamide in 40 ml of methanol/tetrahydrofuran=1/1. The mixture is stirred for 16 hours at room temperature, then the solvents are evaporated off at 15 torr and 40° and 50 ml of methylene chloride are added to the residue. Acidification is effected by adding 50 ml of 1N hydrochloric acid. The organic phase is separated off in a separating funnel. The aqueous phase is extracted twice with 20 ml of methylene chloride each time. The combined organic phases are washed with semi-saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation at 15 torr and 40°. The residue is chromatographed on 45 g of silica gel (Merck, ST 60, 4-63 μm) with 20% hexane in ethyl acetate to yield 1.1 g of the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.90 (s, b, 1H); 8.05 (m, 1H); 7.56 (m, 5H); 7.43 (d, d, 1H); 7.24 (d, 1H); 7.17 (d, d, 1H); 7.15 (d, 1H); 6.96 (s, 1H); 5.08 (m, 1H); 3.97 (s, 2H); 3.92 (s, 3H); 3.68 (s, 3H); 3.47 (t, 2H); 2.47 (t, 2H); 1.92-1.55 (m, 8H); 1.64 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[O:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([OH:19])=[C:21]([O:29][CH3:30])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1cc(B(O)O)ccc1O
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)ccc1O
Yield: 39.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-hydroxy-3-methoxyphenylboronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 91 mg (40%) of the title compound as a white solid. mp 247°-250°. FDMS: m/e=351. α[D]589 =+79.51 (c=0.75, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:31]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.O>[I:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCc1nc(O)c(I)c2cc(OC)c(OC)cc12
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (2.00 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) in dry CH3CN (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was stirred for 10 min at RT before portionwise addition of N-iodosuccinimide (1.82 g, 8.09 mmol) under vigorous stirring. After 2.5 h, the mixture was slowly poured into a cold solution of NaHCO3 (2.0 g) in 50 mL of water and the solid was filtered, washed with water (50 mL) and dried overnight under vacuum to yield 4-iodo-6,7-dimethoxy-1-propylisoquinolin-3-ol CCH 42098-1 as a brown solid (2.35 g, 78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[C:27]([CH:29]([N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])O)#[N:28]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:29]([C:27]#[N:28])[N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])=[O:15]
Reactant: C#CCN1CC(=O)N(C(O)C#N)C1=O
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CCN1CC(=O)N(C(C#N)OC(=O)C(Nc2ccc(C(F)(F)F)cc2F)C(C)C)C1=O
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by the cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol in 5 ml of ether, from part A above, over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate. (A', R is carbonyl, R' is methylene, R1 =R4 is hydrogen, R2 is 2-fluoro-4-trifluoromethylphenyl, R3 is isopropyl, R5 is cyano, R6 is 2-propynyl).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(C)nccn32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@H](c2nc(Br)c3c(C)nccn32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (cis)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (46.8 mmol, 12.8 g) in N,N-dimethylformamide (100 ml) was added N-bromosuccinimide (46.8 mmol, 8.33 g). After stirring at room temperature for one hour the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic layers were washed with water twice, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 3% of methanol) to give (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (15.34 g).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:14]=[C:15]([S:19]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]
Reactant: Cc1cc(O)cc(O)c1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.40 g, 83%). 1H-NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 6.56 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.35 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:33]([O-])(=[O:35])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:18]=[CH:19][C:20]([CH:33]=[O:35])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
N,N-Dimethylformamide (DMF, 250 mL) was added dropwise with stirring under nitrogen to phosphorous oxychloride (115 g, 0.751 mol) at 0° C. The resulting orange solution was stirred for 2 hours, then a solution of 236 g (0.626 mol) of N,N-di-(6-acetoxyhexyl)aniline (A2) in 250 mL of DMF was added slowly. The reaction mixture was stirred under nitrogen for 1 hour at 0° C. and then for 6 hours at 80° C. After cooling, the solution was poured onto 500 g of ice plus 200 g of sodium acetate, and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed four times with 250 mL portions of water, dried over anhydrous sodium sulfate, and then concentrated at reduced pressure to produce a light brown oil. The oil was fractionally distilled in vacuo to yield 192 g (76%) of A3 as a gold oil, bp 220°-260° C. (0.007 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O.C(N(CC)CC)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:14][CH3:15])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC1Oc2ccc(Br)cc2C1(C)C
Yield: 86 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g, 0.02 mole) was heated under reflux in ethanol (30 ml) with sulphuric acid (4 drops) for 11/2 hour. The solution was cooled, neutralised with a few drops of triethylamine and run down. The residue was redissolved in ether and the solution washed with water, dried over magnesium sulphate and the solvent removed under vacuum leaving 4.7 g (86%) title product as a buff-coloured oil. The structure was confirmed by NMR.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.[C:40](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:16][C@H:4]([C@@H:3]([NH:2][C:40](=[O:60])[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:45])([CH3:46])[CH3:44])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)[C@@H](COc1ccc(-n2ccnc2)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To 154 mg (0.31 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide in 3 mL of dimethylformamide, 132 mg (0.31 mmol) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl 4-nitrophenyl carbonate was added, followed by 0.25 mL (1.43 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred for 18 h at room temperature. It was concentrated, a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an methanol:chloroform solution (1:9) to yield 101.3 mg (57%) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate and (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS m/z 574 (M+H) Rt=2.7 min.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.C[Si]([C:25]#[N:26])(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:10][CH:1]([CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:25]#[N:26]
Reactant: N#CC=Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(N)C=Cc1ccccc1
Temperature: -40 °C
Yield: 33 %

Procedure:
10 millimoles (1.29 g) of cinnamonitrile are dissolved in 150 ml of anhydrous toluene at -70° C., under an argon atmosphere. 15 millimoles of a toluenic solution 1.5M of diisobutylaluminum hydride (10 ml) are added, dropwise, at -70° C. The stirring is maintained at this temperature for 30 minutes, then 2 ml of trimethyl-silyl cyanide are added at -40° C. The stirring is then maintained at -40° C. for 2 hours. The reaction mixture is then hydrolyzed at -20° C. with 10 ml methanol and with pasty sodium sulfate. The so-obtained product is purified by liquid chromatography on silica, in eluting with ethyl acetate/petroleum ether 1/1. There are obtained 0.515 g of purified 2-amino-4-phenyl-3-butene-nitrile:yield 33%.
Reaction SMILES: [C:1]([O:5]OC(C)(C)C)(C)(C)C.[C:11]([C:15](=[C:17]([F:19])[F:18])[Br:16])([F:14])([F:13])[F:12]>CO>[C:11]([CH:15]([C:17]([CH2:1][OH:5])([F:19])[F:18])[Br:16])([F:14])([F:13])[F:12]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: FC(F)=C(Br)C(F)(F)F
Solvent: CO
Product: OCC(F)(F)C(Br)C(F)(F)F
Yield: 26 %

Procedure:
In a quartz photochemical reaction vessel equipped with a dry ice condenser, a stirred mixture of methanol (20 g), ditert-butyl peroxide (0.79) and CF3C(Br)═CF2 (10 g, 0.05 mol), was irradiated at 254 nm for ˜6 hr at ambient temperature for under nitrogen. (Note: CF3CBr═CF2 was added as a liquid (BP, 24-25° C.) in one lot before the reaction). Then the reaction mixture was concentrated to remove excess methanol. The concentrated material was taken in ˜40 mL ether, washed with 20 ml 20% aqueous sodium bisulphite followed by brine (10 mL) and distilled to afford the CF3CHBrCF2CH2OH (2.0 g) as a colorless liquid. Yield=26% based on CF3CBr═CF2. Boiling point, 30-31° C./ 8-10 mm Hg. GC-MS: m/e at (C4H4BrF5O) for M+; NMR spectra are consistent with the structure.