Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:9]1([NH:12][CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:11][CH2:10]1
Reactant: O=C1CCC(O)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.3 %

Procedure:
4-hydroxycyclohexanone (443 mg, 3.88 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of cyclopropylamine (0.295 ml, 4.27 mmol), NaBH(OAc)3 (1.3 g, 6.21 mmol), and acetic acid (0.2 ml, 3.88 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 10% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 580 mg of yellow solid (96%).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:26][CH:25]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: COc1ccc(C=O)cc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed overnight in 400 ml of toluene containing 3.5 g of morpholine and 3.4 g of 4-methoxybenzaldehyde. At the end of this time, an additional 1.7 g of aldehyde was added and heating was continued for six (6) more hours. The reaction mixture was then concentrated and purified by flash chromatography (CH2Cl2, then 10% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.37 g of analytically pure material, m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1oc(Br)cc1C=O
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: O
Solvent: COCCOC
Product: Cc1oc(-c2ccnc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 2-chloropyridine-4-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 55%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][CH2:33][CH2:34]CC.C(I)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:33][CH3:34])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (17.5 g, 28.4 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.6 M in hexanes, 19.5 mL, 31.2 mmol) was added keeping the temperature between about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. The mixture was treated with EtI (6.2 mL, 77 mmol) then the temperature of the mixture was raised to about 15° C. over about 5 to 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min at about 20° C. then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL) the layers were separated and then the aqueous layer was extracted with Et2O (100 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was applied to a 120 g silica column and eluted with 9:1 heptane/EtOAc. The fractions largely free of impurities were collected. The impure fractions were combined and evaporated then a second 80 g silica column was run on this material with 9:1 heptane/EtOAc as an eluent to give a second lot of material largely free of impurities. The material from the two columns were combined then further purified by flash chromatography on a 220 g silica gel cartridge with a gradient of 0 to 10% EtOAc/heptane to give 2-bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (7.16 g, 49%): LC/MS (Table 2, Method g) Rt=2.0 min; MS m/z 518 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][NH:13][CH3:14])=[CH:4][CH:3]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[N:32]1([CH2:38][CH2:39][N:40]2[CH2:45][C:44]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52]([OH:54])=O)[CH:48]=[N:49][C:43]=3[NH:42][C:41]2=[O:55])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:31].[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][N:13]([CH3:14])[C:52](=[O:54])/[CH:51]=[CH:50]/[C:47]2[CH:48]=[N:49][C:43]3[NH:42][C:41](=[O:55])[N:40]([CH2:39][CH2:38][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:45][C:44]=3[CH:46]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1ccc(F)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CN(Cc1ccc(F)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting 4-fluoro-naphthalen-1-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.13 g, 43%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.64-10.51 (m, 1H), 10.12 (m, 1H), 8.45-8.30 (m, 1H), 8.22-8.07 (m, 2H), 8.03-7.86 (m, 1H), 7.78-7.62 (m, 2H), 7.63-7.51 (m, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=8.6 Hz, 1H), 7.21-7.12 (m, 1H), 5.03-5.02 (m, 2H), 4.57-4.42 (m, 2H), 4.01-3.91 (m, 2H), 3.80-3.63 (m, 4H), 3.53-3.43 (m, 2H), 3.40-3.25 (m, 2H), 3.09-2.96 (m, 5H); MS (ESI) m/e 504 (M+H)+.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:31])[C:21]=1[CH2:22][OH:23].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:23][CH2:22][C:21]1[C:24]([CH3:31])=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=1[CH3:19])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of tert-butyldiphenylsilyl chloride (30.7 g) in N,N-dimethylformamide (90 ml) were added 2,6-dimethyl-3-nitrobenzyl alcohol (18.4 g) and imidazole (8.99 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 3 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67 g) as pale yellow oil.
Reaction SMILES: C(=O)([O-])N.[C:5]([O:9][C:10]([N:12]([C:20]1[C:25]([CH3:27])([CH3:26])[S:24](=[O:29])(=[O:28])[C@@H:23]([CH2:30][C@@H:31]([OH:33])[CH3:32])[C@:22]([C:35]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=2F)([CH3:34])[N:21]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:27][C:25]1([CH3:26])[S:24](=[O:29])(=[O:28])[C@@H:23]2[CH2:30][C@H:31]([CH3:32])[O:33][C:36]3[CH:37]=[CH:38][C:39]([N+:41]([O-:43])=[O:42])=[CH:40][C:35]=3[C@@:22]2([CH3:34])[N:21]=[C:20]1[N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: C[C@H](O)C[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A mixture of cis and trans isomers, tert-butyl N-tert-butoxycarbonyl-N-[2R,3R)-3-(2-fluoro-5-nitro-phenyl)-2-[(2S)-2-hydroxypropyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate and tert-butyl N-tert-butoxycarbonyl-N-[(2S,3R)-3-(2-fluoro-5-nitro-phenyl)-2-[(2S)-2-hydroxypropyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (1.8 g, 3.06 mmol) and cesium carbonate (4.99 g, 15.32 mmol) were combined in DMSO (15 ml) and stirred at room temperature for 6 h. The solution was diluted with water and the precipitate was collected by filtration, washed with water, and dried under vacuum. The product was purified via silica gel column chromatography (80 g column) using 10-50% ethyl acetate in heptane to afford to afford tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.62 g, 2.85 mmol, 93% yield). MS m/z=590 [M+Na].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8].C(O[CH2:18][C:19]([CH2:21][Si](C)(C)C)=[CH2:20])(=O)C>C1COCC1.CCCCCC.[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.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]=[C:19]1[CH2:21][C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:5]([C:4]2[CH:11]=[CH:12][CH:13]=[C:2]([F:1])[CH:3]=2)[CH2:20]1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COC(=O)/C=C/c1cccc(F)c1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of methyl trans-3-fluorocinnamate (41.25 g, 229 mmol), tetrakis(triphenylphosphine) palladium(0) (18.5 g, 16 mmol), 1,2-bis(diphenylphosphino)ethane (5.5 g, 13.7 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (42.66 g, 229 mmol) in THF (300 mL) under nitrogen was heated to reflux for 6 h and then stirred at rt for 16 h. The reaction was diluted with hexane and filtered to remove yellow precipitate. The volatiles were then removed in vacuo and the residue was purified by FC (3 to 5% ethyl acetate in hexanes) to afford the title compound (45 g).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH2:32]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CC1CNc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)c2ccccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 61 mg (0.37 mmol) 3-methyl-2,3-di-hydro-1H-indole, 150 μL (0.87 mmol) DIPEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.N1C=CN=C1.C(OCC)C>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
tert-Butyldimethylsilyl chloride (1.8 g) was added over 30 minutes to a stirred solution of 4-bromo-4'-hydroxybiphenyl (2.49 g) and imidazole (1.63 g) in dimethylformamide (15 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (225 ml) was added, the ether washed with saturated sodium hydrogen carbonate solution (3×60 ml) and brine (100 ml), dried (MgSO4) and evaporated to yield, as a colourless oil, 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (3.2 g); NMR (CDCl3): 0.2(6H, s), 1.0(9H, s), 6.8-6.9(2H, d), 7.3-7. 4(4H, m) and 7.45-7.55(2H, d).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:23].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([I:23])=[CH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(I)=Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of acetylene from step 1 (8.79 g, 30 mmol) in dichloromethane (600 mL) at room temperature there was added a solid mixture of sodium iodide (18 g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with aqueous 1N NaOH (600 mL) and stirred vigorously for 15 min. The organic phase was collected and washed 3 times with water, dried and evaporated to a residue which was stirred in a 2:1 mixture of hexane and ether (100 mL) for 2 h and filtered to afford the desired vinyl iodide (8.46 g, 67%) as a beige solid, assayed by NMR to be a 4:1 mixture of Z and E isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[C:17]([O:20][CH2:21][CH2:22][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OCCBr
Reactant: O=Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOc1ccc(C=O)cc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzaldehyde (2.0 g, 14.3 mmol), K2CO3 (5.92 g, 42.8 mmol) and 2-bromoethyl acetate (4.77 g, 28.5 mmol) in acetone (30 mL) is stirred at 55° C. for 24 h before it is diluted with diethyl ether (150 mL) and washed with water (3×50 mL). The organic extract is dried over MgSO4 and concentrated. The remaining residue is chromatographed on silica gel to give the title aldehyde (1.65 g) as a colourless oil. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.64-7.58 (m, 2H), 7.07 (t, J=8.2 Hz, 1H), 4.49-4.45 (m, 2H), 4.35-4.30 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[NH:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20].[N:22]([O-])=[O:23].[Na+]>C(O)(=O)C>[CH3:1][N:2]([N:22]=[O:23])[C:3](=[O:21])[NH:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20]
Reactant: O=N[O-]
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)N(C)N=O)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 4 (1.00 g, 3.35 mmol) in 50% aqueous acetic acid at 0°, sodium nitrite (0.31 g, 4.55 mmol) was added slowly. The reaction mixture was kept at 0° with stirring for 3 h, during which time crystals started to precipitate out. The product was collected by filtration, washed with water, cooled methanol, ether, and dried. The filtrate was concentrated and an additional fraction of crystals was obtained. The combined product was recrystallized from methanol to yield 0.77 g (70%) of white fine needles: mp 159°-160° dec.: uvλmaxEtOH 264 nm (ε11,000); uvλminEtOH 235 nm. Anal. (C12H17N5O6) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6](O)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O>C(OCC)C>[Cl:21][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:8][CH2:7]1
Reactant: OC1CCOc2cc(F)ccc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1ccc2c(c1)OCCC2Cl
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of 7-fluorochroman-4-ol (1.80 g, 10.7 mmol, STEP 1) and pyridine (0.35 mL) in diethyl ether (14 mL) was added thionyl chloride (3.9 mL, 53.5 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 3 hours, and evaporated to remove excess thionyl chloride. The residue was quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum to afford the title compound as a pale brown solid (2.0 g, quant.):
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].Cl.[NH:13]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[NH2:14]>CO>[NH2:5][C:4]1[N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:14]=[C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1
Reactant: CCOC(=O)CNN
Reactant: N#CCC(=O)c1cccnc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1nc(-c2cccnc2)cc1N
Temperature: 120 °C
Yield: 24.4 %

Procedure:
A mixture of 3-oxo-3-pyridin-3-ylpropane nitrile (1.31 g, 9 mmol), ethyl hydrazinoacetate hydrochloride (1.39 g, 9 mmol) in methanol (9 mL) was heated under microwave irradiation at 120° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate) yielding the title compound as a solid (510 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:43][O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>CC(O)C>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)[C:11]([N:49]3[CH2:50][CH2:51][CH:47]([C:45]([O:44][CH3:43])=[O:46])[CH2:48]3)=[N:12][CH:13]=2)=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)C1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
DIPEA (181 μL, 1.035 mmol) was added to a mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 36.1, 100 mg, 0.207 mmol), methyl-3-pyrrolidine carboxylate hydrochloride (44.5 mg, 0.269 mmol) and iPrOH (414 μL). in MW vial, which was flushed with argon, sealed and stirred at 130° C. for 24 h. The RM was diluted with EtOAc, treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc) followed by preparative TLC (Silica gel, eluent EtOAc). Additional lyophilization from 1,4-dioxane afforded the title compound as a white light solid. UPLC-MS (Condition 6) tR=1.09 min, m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.06-3.20 (m, 1H) 3.23-3.48 (m, 4H) 3.61 (s, 3H) 6.35-6.48 (m, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.79-7.90 (m, 1H) 7.89 (d, J=8.80 Hz, 2H) 8.03-8.13 (m, 1H) 8.70-8.83 (m, 1H) 10.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]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>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][CH:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:28])[CH2:33][CH2:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC2CCOCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl tetrahydropyran (34.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (10.8 mg, 10.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C29H35Cl2N3O2S+H [(M+H)+]: 528.2179. found: 528.2180.