Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1c([N+](=O)[O-])ccc(Cl)c1Cl
Yield: 43.6 %

Procedure:
By the same procedure described for Example 7 A, from 0.86 g of 2,3,4-trichloro-nitro-benzene and 1.0 g of 4-carbobenzyloxypiperazine-2-carboxylic acid, there was obtained 0.75 g of the desired product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[CH:33]3)=[O:29])[CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[C:37]([CH3:39])[CH:38]=5)[N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[N:34]=[CH:33]6)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(COCC[Si](C)(C)C)c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5COCC[Si](C)(C)C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36 mg (0.13 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.12 mmol) (6-chloro-pyrimidin-4-yl)-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-indazol-5-yl]-methanone and 30 μL (0.21 mmol) TEA were combined in 0.5 mL DMF and stirred overnight at RT. The reaction mixture was mixed with ice water, the product precipitated as a solid was filtered off and dried.
Reaction SMILES: CO[C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[OH:39][CH2:40][CH2:41]NCCO>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([N:5]([CH2:41][CH2:40][OH:39])[CH2:4][CH2:3][OH:38])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: OCCNCCO
Product: O=C(c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl)N(CCO)CCO
Yield: 71 %

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-(2-hydroxy-ethylamino)-ethanol (commercially available, CAS RN 111-42-2). The product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown solid (71%). MS (ESI): m/z=571.150 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:35][N:18]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:6][CH2:5][C:4]([OH:36])=[O:3])[C:19](=[O:34])[C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: CCOC(=O)CCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 30 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pentanoic acid ethyl ester and 3.7 g of lithium hydroxide in 210 ml of tetrahydrofuran/methanol/water=2/2/1 is stirred at room temperature for 3 hours and then concentrated by evaporation. The residue is dissolved in 300 ml of water, extracted with ether, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:27])=[C:11]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:17])[CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:28]=O>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:16]([C:11]2[CH:12]=[N:13][C:14]3[C:9]([C:10]=2[OH:27])=[CH:8][CH:7]=[C:6]([N:2]([CH3:1])[CH3:28])[CH:15]=3)=[O:17])=[CH:21][CH:22]=1
Reactant: C=O
Reactant: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reaction time: 0.17 h

Procedure:
Sodium cyanoborohydride (96 mg) is added to a mixture of 100 mg 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide and 91 mg paraformaldehyde in 5 mL of acetic acid. After 2 days the mixture is diluted with 5 mL of distilled water (use of more water causes the product to precipitate as an oil). The mixture is stirred an additional 10 min and then the product is collected by filtration. It is washed with three 1 mL portions of 50% aqueous acetic acid and dried in a stream of air. It is dried at 20 torr/24 h/75° C. The product is obtained as mg of an off-white powder.
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([CH:60]3[CH2:62][CH2:61]3)(=[O:59])=[O:58])=[CH:53][CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:52]=[CH:53][C:54]([S:57]([CH:60]3[CH2:61][CH2:62]3)(=[O:59])=[O:58])=[CH:55][CH:56]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(=O)(=O)C3CC3)cc2)c2c(c1)OC(C)(CO)C2
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(S(=O)(=O)C4CC4)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (245a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C25H30O7S m/z 475.20 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13]([OH:15])=O)[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:13]([C@H:12]1[CH2:11][N:10]([CH3:16])[C:9](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:15])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: CN1C[C@H](C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)N(Cc2ccccc2)C1=O

Procedure:
Coupling of (R)-3-Benzyl-1-methyl-2-oxo-imidazolidine-4-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:30]([S:31]([CH:34]([CH3:35])[CH3:36])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(=O)(=O)C(C)C)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product was obtained as a pale foam (32 mg, 22%). LCMS: 550.09 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ 8.11 (d, J=11.6 Hz, 1H), 8.10 (s, 1H), 7.83-7.81 (m, 1H), 7.49-7144 (m, 3H), 7.11-7.08 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 3.60.3.56 (m, 2H), 3.37 (s, 3H), 3.10-3.00 (m, 1H), 2.88-2.74 (m, 8H), 2.08-2.06 (m, 2H), 1.22 (d, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][OH:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][O:29][CH3:32])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(Oc2ccccc2CO)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccccc1OC(c1ccccc1)C1CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
2-[(2-Hydroxymethyl-phenoxy)-phenyl-methyl]-morpholine-4-carboxylic acid tert-butyl ester (0.44 g) was taken up in THF (10 mL) and placed in a room temperature bath for the addition of NaH (0.05 g). The mixture was stirred for 10 min, and then MeI (0.17 g) was added and stirred at room temperature for 3 h. The mixture was again treated with NaH and MeI and stirred at room temperature for 48 h. Starting material was still present, so the mixture was treated with NaH. MeI was passed through a plug of basic alumina and then added. After 3 h, the reaction was carefully quenched by the addition of water. The mixture was extracted with ether (3×30 ml), and the organics were combined, washed with brine (1×20 ml), dried over MgSO4, filtered and concentrated. The colorless oil was taken up in DCM and pumped onto silica and then purified by MPLC (Hexane:EtOAc 95:5 to 40:60). Fractions containing the desired product were combined and concentrated to give 0.317 g of Preparation of 2-[(2-Methoxymethyl-phenoxy)-phenyl-methyl]-morpholine-4-carboxylic acid tert-butyl ester (70% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH:19](I)([CH3:21])[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH:19]([CH3:21])[CH3:20])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.5 ml of tert-butyl diethylphosphonoacetate are dissolved in 20 ml of dimethylformamide, and 820 mg of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0° C. The suspension is stirred at 0° C. for 15 minutes, and 2.4 ml of isopropyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=5:1. This gives 4.2 g of tert-butyl 2-(diethoxyphosphoryl)-3-methylbutyrate as an oil. C13H27O5P (294.33), MS(ESI): 239 (M-C4H8+H+), Rf(n-heptane:ethyl acetate=1:1)=0.34.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].CN(C=O)C.S([O-])(O)(=O)=O.[Na+].O>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](/[N:19]=[CH:3]/[N:4]([CH3:6])[CH3:5])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: COC(OC)N(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (14.6 mL, 104 mmol) was added to a solution of 2-bromobenzene-1-sulfonamide (20.4 g, 86.4 mmol) in DMF (56 mL, 720 mmol) and the resulting solution was stirred at room temperature for 90 minutes. A solution of sodium hydrogen sulfate (1.7 g, 14 mmol) in water (170 mL, 9.4 mol) was cooled at 0° C. and then added to the reaction mixture. The precipitate was filtered, washed with water, and dried to yield the title compound (24.3 g) as a white solid.
Reaction SMILES: O1CCCC1.B.[CH:7]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[C:22](=O)[CH2:23][CH2:24][O:25][CH3:26])[CH2:9][CH2:8]1.[OH-].[Na+].CO>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][NH:10][CH:7]3[CH2:8][CH2:9]3)[CH:13]=2)[N:17]([CH3:21])[CH:16]=1
Reactant: COCCC(=O)c1cn(C)c2ccc(CNC3CC3)cc12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCc1cn(C)c2ccc(CNC3CC3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
A 1M tetrahydrofuran-solution of borane tetrahydrofuran (2.62 ml) was added dropwise to a solution of 1-{5-[(cyclopropylamino)methyl]-1-methyl-1H-indol-3-yl}-3-methoxy propan-1-one (150 mg) in tetrahydrofuran (2.5 ml) under ice-cooling and the mixture was stirred at room temperature for 15 hours. A 5N aqueous solution of sodium hydroxide (2.5 ml) and methanol (1.25 ml) were added to the reaction mixture and it was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, extracted with diethyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform to chloroform/methanol=5/1) to give N-{[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]methyl}cyclopropanamine (107 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O[CH:22]=[C:23]1[C:34]2[C:26](=[CH:27][CH:28]=[C:29]3[C:33]=2[S:32][CH:31]=[N:30]3)[NH:25][C:24]1=[O:35])C>>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:22]=[C:23]2[C:34]3[C:26](=[CH:27][CH:28]=[C:29]4[C:33]=3[S:32][CH:31]=[N:30]4)[NH:25][C:24]2=[O:35])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CN(CCOCCO)S(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz,1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21 H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:37]([C:40]3([C:43]([F:46])([F:45])[F:44])[CH2:42][CH2:41]3)=[CH:38][N:39]=[C:34]2[C@H:33]([NH2:47])[CH2:32][CH2:31]1.[O:48]=[C:49]1[NH:57][C:52]2=[N:53][CH:54]=[CH:55][CH:56]=[C:51]2[C:50]21[CH2:65][C:64]1[C:59](=[CH:60][CH:61]=[C:62]([C:66](O)=[O:67])[CH:63]=1)[CH2:58]2>CN(C)C=O>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:37]([C:40]3([C:43]([F:46])([F:44])[F:45])[CH2:42][CH2:41]3)=[CH:38][N:39]=[C:34]2[C@H:33]([NH:47][C:66]([C:62]2[CH:63]=[C:64]3[C:59](=[CH:60][CH:61]=2)[CH2:58][C:50]2([C:51]4[C:52](=[N:53][CH:54]=[CH:55][CH:56]=4)[NH:57][C:49]2=[O:48])[CH2:65]3)=[O:67])[CH2:32][CH2:31]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
Triethylamine (18.0 μL, 0.129 mmol), EDC (17 mg, 0.086 mmol), and HOBT (7.0 mg, 0.043 mmol) were added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine from Step A (16 mg, 0.043 mmol) and the hydrochloride salt of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (14.0 mg, 0.043 mmol, described in Intermediate 2) in N,N-dimethylformamide (1 mL). After 18 h, the reaction mixture was filtered and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—95:5:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=634 (M+1). HRMS: m/z=634.2265; calculated m/z=634.2236 for C34H29F5N5O2.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Br:6]>CC(C)=O>[Br-:6].[O:9]1[CH2:8][CH:7]1[CH2:5][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: BrCC1CO1
Reactant: CN(C)C
Solvent: CC(C)=O
Product: C[N+](C)(C)CC1CO1
Product: [Br-]
Temperature: 10 °C
Reaction time: 60 h
Yield: 93.4 %

Procedure:
A flask equipped with a sparger, mechanical stirrer, thermometer and efficiency condenser was charged with acetone (500 milliliters) at ambient temperature. Trimethylamine (58 grams, 0.98 mol) was charged into the solution. The pot was cooled to 10° C. and epibromohydrin (137 grams, 1.0 mol) was added dropwise over a 1 hour period. The resultant cloudy solution was allowed to slowly rise to ambient temperature and stand for 60 hours. Precipitate was collected by filtration washed with acetone (60 milliliters) and dried yielding a colorless crystalline product (179.4 grams, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=[O:10])[C:2]=12.[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH:26][C:7]([C:3]4[C:2]([C:9]([OH:8])=[O:10])=[N:1][CH:6]=[CH:5][N:4]=4)=[O:11])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: O=C1OC(=O)c2nccnc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)c1nccnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 78 °C
Yield: 46.3 %

Procedure:
Furo[3,4-b]pyrazine-5,7-dione (736 mg, 4.9 mmol) and DMAP (58 mg, cat.) were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 1.00 g, 4.8 mmol) in DMF (25 ml). The mixture was heated to 78° C. overnight, and cooled to RT. The formed precipitate was collected by filtration, and residual solvent was removed under vacuum. The thus obtained crude product (800 mg, 47%) was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C@@:6]2([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]([C@H:4]([N:11]3[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]3=[O:13])[O:5]2)[O:2]1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([O:10][CH2:9][C@@:6]23[CH2:1][O:2][C@@H:3]([C@H:4]([N:11]4[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]4=[O:13])[O:5]2)[C@@H:7]3[OH:8])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To Compound 7 (140 mg, 0.53 mmol), anhydrous pyridine was added, followed by performing azeotropy of the mixture 3 times. Then, the product was converted into an anhydrous pyridine solution (1.5 ml), and 4,4′-dimethoxytrityl chloride (210 mg, 0.63 mmol) and DMAP (6.5 mg, 0.053 mmol) were added at room temperature in a stream of nitrogen. The mixture was stirred for 5 hours at room temperature. To the reaction mixture, a saturated sodium bicarbonate solution was added, followed by extraction with CH2Cl2. The organic phase was washed with water and a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvents were distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (CHCl3:MeOH=40:1) to obtain Compound 8 (230 mg, 0.34 mmol, 66%).