Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11]OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: Oc1ccccc1Cl
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccccc1Cl
Reaction time: 72 h

Procedure:
2-Chlorophenol (96.4 g, 0.75 mol), dimethoxymethane (257.9 g, 3.39 mol) and 750 mg of p-toluenesulfonic acid were dissolved in 1.5 L of methylene chloride and the mixture heated at reflux with stirring under nitrogen for 72 hours in a flask equipped with a Soxhlet extraction apparatus containing 400 g of 3A molecular sieves. The mixture was allowed to cool and 3 ml of triethylamine was added. The mixture was then extracted with 2N sodium hydroxide and the organic phase was dried over magnesium sulfate. Evaporation of the volatiles under reduced pressure left 66.9 g of crude 1-chloro-2-methoxymethoxybenzene as a residue. This was distilled and the fraction boiling at 94° C. and 6.5 mm pressure was collected to obtain 51.3 g (40 percent of theory) of purified product. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38]CC)=O)[CH2:31][CH2:30]2)[C:9]=1Br.O.[NH2:53][NH2:54]>CN(C=O)C>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][CH:32]([CH2:35][C:36]([NH:53][NH2:54])=[O:38])[CH2:33][CH2:34]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)CC1CCC(c2cc(N)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a 2-5 mL pressure vial was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (0.12 mmol, 95 mg), DMF (1 mL), and hydrazine monohydrate (1 mL). The pressure vial was sealed and heated to 80° C. for 18 hours. After 18 hours, the solvents were removed in vacuo and the product taken on without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH2:19].CO>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][CH2:17][O:16][C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COc1ccccc1OCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1OCCNc1ccc2ncc(Br)n2n1
Temperature: 160 °C
Yield: 44.1 %

Procedure:
A mixture of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1 mmol) and 2-(2-methoxy-phenoxy)-ethylamine (2 g, 12 mmol) was heated in a microwave at 160° C. for 30 min. The reaction mixture was subjected to ISCO (40 g column, DCM 3 min. then 0-10% MeOH in DCM over 30 min.) to gave the product (160 mg). LRMS (ESI) m/z 363 and 365.1 [(M+H)]+, calc'd for C15H15BrN4O2: 363.22.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C([O-])(=O)C.[NH4+:17].O>C(O)CO>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC(=O)[O-]
Solvent: OCCO
Solvent: O
Product: Nc1cc(=O)oc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
97.2 g of 4-hydroxycoumarin and 69.3 g of ammonium acetate in 300 ml of ethylene glycol are heated to 70° C. for 3 hours, whilst stirring, and to 160° C. for 6 hours, the mixture is cooled to 60° C., 1 liter of water is added, whilst stirring, and the mixture is cooled to room temperature. The colourless crystalline precipitate is filtered off, washed with water and dried in vacuo at 60° C. 96 g of 4-aminocoumarin in an almost pure form are obtained
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)c1cccn1CC2
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9amino-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one in triethyl orthoformate (2.14 g.; 10 mmoles in 80 ml) is refluxed for 5 hours. The volatiles are removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g.; 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hours. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino -6,11 -dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)Cl.N1C=CC=CC=1.[C:29]1([C@@H:35]2[CH2:37][C@H:36]2[C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:38]([CH:36]4[CH2:37][CH:35]4[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:39])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CC3c3ccccc3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (50.5 mg, 0.200 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.04 mL, 0.5 mmol) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (35.0 uL, 0.225 mmol). The reaction mixture was stirred at room temperature for one hour and then evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 29.1 mg (37%) of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)-2-phenylcyclopropanecarboxamide (mixture of trans stereoisomers). LCMS (ESI): RT (min)=6.288, M+H=397.1, Method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.17 (s, 1H), 8.54 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.38 (t, J=7.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 2H), 7.25-7.12 (m, 5H), 2.47-2.40 (m, 2H), 2.25 (s, 3H), 1.60-1.48 (m, 1H), 1.39 (dd, J=11.0, 7.4 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[CH:22][CH:21]=1>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[N:4][C:3]=1[CH2:2][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[CH:24][CH:25]=1
Reactant: N#CCCCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole was allowed to react with 4-(4-hydroxyphenyl)butyronitrile to give 4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]butyronitrile. Recrystallization from chloroform-ether gave colorless prisms, m.p.149°-151° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19](OC(C)(C)C)=[O:20])[CH:14]=2)=[CH:10][C:9]=1[F:28]>C1COCC1>[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)=[CH:10][C:9]=1[F:28]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(CO)c2)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of LiAlH4 (699 mg, 18.4 mmol) in THF (15 mL) was added tert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (1.4 g, 4.6 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with 10% aq NaOH solution (4 mL), the resultant suspension was filtered and the filtrate was extracted with EtOAc (3×30 mL) to give (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (700 mg, 70% yield). MS (ESI) m/z: 235.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH2:10][CH3:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCc1sc(N)c(C#N)c1C
Product: CCc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in example 1a from 2-amino-5-ethyl-4-methylthiophene-3-carbonitrile (example 7b) and benzoyl isocyanate as a pale-yellow solid. MS 314 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CCl)ccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(CC#N)ccc1Br

Procedure:
4-Bromo-3-methoxybenzyl chloride (23.5 g, 0.1 m) dissolved in ethanol (500 ml) is treated with potassium cyanide (13 g, 0.2 m) dissolved in water. The mixture is warmed and stirred to give 4-bromo-3-methoxyphenylacetonitrile.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[CH3:20][NH:21][O:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9](=[O:10])[NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]([O:22][CH3:23])[CH3:20])[N:4]=1
Reactant: CNOC
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Yield: 86 %

Procedure:
A mixture of Intermediate 4: 2-(3-(3-fluorobenzyl)ureido)-4-chloromethyl-thiazole (40 g, 0.133 mol), N,O-dimethylhydroxylamine (80 g, 0.820 mol), sodium carbonate (40 g, 0.754 mol), and abs. EtOH (0.2 L) was stirred and heated at 60-70 C for 8-12 hours. The mixture was diluted with water (0.8 L) and cooled to 20 C with continued stirring. The solids were collected by filtration, washed with water, and dried in vacuo to afford the title compound (37 g, 86% yield).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Br[CH2:18][C:19]([O:21]CC)=[O:20]>>[C:19]([CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)([OH:21])=[O:20]
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: CCOC(=O)CBr
Product: O=C(O)COc1ccc2sc3ccccc3c(=O)c2c1
Yield: 75 %

Procedure:
An example of a conventional synthetic route to 2-carboxymethoxythioxanthone involves three stages. Firstly, phenol is reacted with dithiobisbenzoic acid to produce 2-hydroxythioxanthone in a 60% yield. Secondly, the 2-hydroxythioxanthone is reacted with ethyl bromoacetate to produce the ethyl ester of 2-carboxymethoxythioxanthone in 75% yield. Thirdly, the ester is hydrolysed by acidification to produce the desired product in 90% yield. These three stages form an inefficient and time-consuming process to provide a product that is a dark colour, contains impurities and by-products and is produced with only an overall yield of 40% from the starting material.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccccc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N(CC1CN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of N-(1-Boc-Azetidine-3-ylmethyl)aniline 48 (218.6 mg, 0.791 mmol) and piperidinomethyl polystyrene resin (250 mg) in 2 mL of dry CH2Cl2 was added propionyl chloride (77 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2 Removal of CH2Cl2 afforded N-(1-Boc-azetidine-3-ylmethyl)-N-phenylpropionamide 49 (241 mg, 96%).
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl N-[(pent-4-enyloxy)carbonyl]-L-norleucinate (8.50 g, 33.03 mmol) in THF (20 mL) was added 1N NaOH (20 mL). This reaction solution was stirred at r.t. for 3 h, then acidified to pH 3 with 1N HCl and extracted with (3×250 mL) EtOAc. The combined EtOAc layer was washed with 50 mL water, 50 mL brine, dried over sodium sulfate, filtered and concentrated to give 7.09 g (88%) of the title product as clear oil. LRMS (ESI) m/z 244 [(M+H)+; calcd for C12H22NO4: 244].
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)C>CCCCCCC>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCCCCCC
Solvent: CC(C)O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C
Yield: 76.2 %

Procedure:
5 g (17.79 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid was put in suspension in 6.8 mL (0.06 mole) of N-methyl piperazine. The reaction mixture was heated to reflux for 40 minutes until completion of the reaction. The mixture was then cooled to 80° C. IPA (10 mL) and n-heptane (10 mL) were added at this temperature. The solid was filtrated under vacuum and rinsed with n-heptane. The mother liquor also gave a precipitate after addition of n-heptane. Both precipitates were filtrated under vacuum and dried overnight to yield 4.9 g (76%) levofloxacin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[C:10]([CH:27]=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[C:10]([CH2:27][OH:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2c(C(=O)OCc3ccccc3)cccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CO)c2c(C(=O)OCc3ccccc3)cccc21
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonyl-3-formylindole-4-carboxylate (363 mg) in methanol (15 ml) was added sodium borohydride (109 mg) at 0° C. and the mixture was stirred for 5 minutes. The resulting mixture was diluted with water and the solution was neutralized with 1N hydrochloric acid. The solution was extracted with ethyl acetate, and then the organic solution was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and concentrated in vacuo to afford benzyl 1-tert-butoxycarbonyl-3-hydroxymethylindole-4-carboxylate (365 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([O:22][CH3:23])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][O:22][CH3:23])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with methyl propargyl ether (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (503 mg, 83.8%) as an amber oil: EI-HRMS m/e calcd for C19H24O3 (M+) 300.1725, found 300.1728.
Reaction SMILES: [NH:1]1[CH2:6]CC[CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17].CS(Cl)(=O)=O>>[C:16]([N:1]1[CH2:2][CH2:3][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6]1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)Cl
Product: CC(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl chloride for methanesulfonyl chloride in EXAMPLE 147A.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23](O)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NOC1CCCCO1)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (0.116 g, 0.316 mmol) and O-(tetrahydropyran-2-yl)hydroxylamine (0.0407 g, 0.347 mmol) in methylene chloride (2.5 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.144 g, 0.379 mmol) and N-methylmorpholine (0.1 mL, 0.9 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue obtained purified via silica chromatography (80-100% EtOAc/hexane) to afford Intermediate 21 as a clear colorless oil (0.152 g, 100%). LC-MS: (FA) ES+466.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[CH2:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCCC2
Reaction time: 96 h
Yield: 8.6 %

Procedure:
10% w/w Palladium-on-carbon (10 g) was added to a solution of 1-naphthoic acid (33.4 g) in glacial acetic acid (150 ml) and the mixture hydrogenated at 345 kPa (50 psi) and 85° C. for 4 days. The warm mixture was filtered through a short column of Arbacel (trade mark) filter aid and the pad washed with glacial acetic acid (150 ml). Water (1.5L) was added to the filtrate and the resulting precipitate filtered off and washed with water. The precipitate was dissolved in dichloromethane, the solution dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give an oil which was crystallised from ethyl acetate to give 1,2,3,4-tetrahydro-5-naphthoic acid (2.94 g) as a white solid (m.p. 148-150° C.).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+]>O.C(O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:9]2[CH2:10][CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)cc2)CCCC1c1ccccc1
Yield: 95.3 %

Procedure:
Fifty grams of 2-phenylcyclohexanone, 54.0 g of 4-chlorobenzaldehyde and a solution of 20 g of sodium hydroxide in 125 ml of water are reacted in 300 ml of ethanol according to the procedure described in part A of Example 1 to yield 81.2 g of material, melting point 103°-109° C. After crystallization from 100 ml of acetonitrile, the crystalline product weighs 61.6 g, melting point 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:26][CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])[C:2]([Cl:1])=[CH:3][C:4]=2[O:26][CH3:27])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of tert-butyl 4-(2-(4-chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazine-1-carboxylate (200 mg, 0.4 mmol) and 2-chlorophenylboronic acid (69 mg, 0.44 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (212 mg, 2 mmol) were added. The mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desire product (150 mg, 76% yield).